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, according to a study in Clinical Gastroenterology and Hepatology.
The new morphometric duodenal biopsy mucosal scale joins together villous height-to-crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) — each key CeD histological measures of the small intestine — in a scale called VCIEL.
The authors believe the VCIEL will enable a broader and more accurate measurement of mucosal health in CeD. It will be particularly useful for population analysis in clinical trials and could improve the powering of trial design. “Use of VCIEL may lead to better outcome measures for potential new therapeutic treatments benefiting patients,” wrote Jocelyn A. Silvester, MD, PhD, a pediatrician at Boston Children’s Hospital and an assistant professor at Harvard Medical School, and colleagues.
This chronic enteropathy affects about 1% of the world’s population and requires a lifelong adherence to a gluten-free diet, the authors noted.
The authors pointed to weaknesses in the current quantitative and qualitative ways of measuring gluten-induced mucosal injury on biopsy for CeD. “Morphometry measures the injury continuum for architecture and inflammation, but these are used as separate outcomes,” they wrote. “The original Marsh-Oberhuber [M-O] classifications are rather contrived approaches to assess a biologic continuum, forcing the injury in categorical groups of unclear clinical relevance and where clinically significant changes may occur within one single category.”
Moreover, the quantitation of inflammation relies on binary assessment as normal or increased, which results in histology that is unscorable by M-O if villous atrophy persists without increased IELs, they added.
The Study
In the absence of a broadly accepted single measure of mucosal injury in CeD, the group assessed whether the composite metric could improve statistical precision for assessing histology.
Enter VCIEL, which combines the Vh:Cd and IEL for individual patients with equal weighting by converting each scale to a fraction of their standard deviation and summing the results.
The researchers applied the VCIEL formula in a reanalysis of four clinical gluten-challenge trials and compared the results for Vh:Cd and IEL separately with those for VCIEL for clinical significance (effect size) and statistical significance.
In reanalysis of the ALV003-1021 trial, for example, the researchers observed an effect size and P value (analysis of covariance) of 1.37 and .038 for a delta (difference) value of Vh:Cd 1.17 and .005 for IEL and 1.86 and .004 for VCIEL.
For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding delta results were .76 and .057 for Vh:Cd, .98 and .018 for IEL, and 1.14 and .007 for VCIEL. Comparable improvements with VCIEL over individual Vh:Cd and IEL were observed for other studies, including a nontherapeutic gluten challenge study.
In NCT03409796 trial data, the computation of VCIEL values showed an improved statistical significance relative to the component values of Vh:Cd and IEL by the within-group paired 2-tailed t test P values from baseline to day 15, particularly at a 10-g gluten challenge dose: Vh:Cd, IEL, VCIEL = .0050, .0031, and .0014, respectively.
Little correlation emerged between baseline values and changes with intervention for Vh:Cd and IEL on an individual patient basis.
The greater accuracy and statistical precision of the VCIEL scale are presumably due to averaging over some of the measurement uncertainty in individual patient and timepoint Vh:Cd and IEL values and creating a composite of different histologic properties, the authors noted.
This study was funded by ImmunogenX, Inc. First author Jack A. Syage is a cofounder and shareholder in ImmunogenX Inc. Dr. Silvester has served on an advisory board for Takeda Pharmaceuticals and has received research funding from Biomedal S.L., Cour Pharmaceuticals, and Glutenostics LLC. Several coauthors disclosed various financial ties to multiple private-sector pharmaceutical and biomedical companies, including ImmunogenX.
, according to a study in Clinical Gastroenterology and Hepatology.
The new morphometric duodenal biopsy mucosal scale joins together villous height-to-crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) — each key CeD histological measures of the small intestine — in a scale called VCIEL.
The authors believe the VCIEL will enable a broader and more accurate measurement of mucosal health in CeD. It will be particularly useful for population analysis in clinical trials and could improve the powering of trial design. “Use of VCIEL may lead to better outcome measures for potential new therapeutic treatments benefiting patients,” wrote Jocelyn A. Silvester, MD, PhD, a pediatrician at Boston Children’s Hospital and an assistant professor at Harvard Medical School, and colleagues.
This chronic enteropathy affects about 1% of the world’s population and requires a lifelong adherence to a gluten-free diet, the authors noted.
The authors pointed to weaknesses in the current quantitative and qualitative ways of measuring gluten-induced mucosal injury on biopsy for CeD. “Morphometry measures the injury continuum for architecture and inflammation, but these are used as separate outcomes,” they wrote. “The original Marsh-Oberhuber [M-O] classifications are rather contrived approaches to assess a biologic continuum, forcing the injury in categorical groups of unclear clinical relevance and where clinically significant changes may occur within one single category.”
Moreover, the quantitation of inflammation relies on binary assessment as normal or increased, which results in histology that is unscorable by M-O if villous atrophy persists without increased IELs, they added.
The Study
In the absence of a broadly accepted single measure of mucosal injury in CeD, the group assessed whether the composite metric could improve statistical precision for assessing histology.
Enter VCIEL, which combines the Vh:Cd and IEL for individual patients with equal weighting by converting each scale to a fraction of their standard deviation and summing the results.
The researchers applied the VCIEL formula in a reanalysis of four clinical gluten-challenge trials and compared the results for Vh:Cd and IEL separately with those for VCIEL for clinical significance (effect size) and statistical significance.
In reanalysis of the ALV003-1021 trial, for example, the researchers observed an effect size and P value (analysis of covariance) of 1.37 and .038 for a delta (difference) value of Vh:Cd 1.17 and .005 for IEL and 1.86 and .004 for VCIEL.
For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding delta results were .76 and .057 for Vh:Cd, .98 and .018 for IEL, and 1.14 and .007 for VCIEL. Comparable improvements with VCIEL over individual Vh:Cd and IEL were observed for other studies, including a nontherapeutic gluten challenge study.
In NCT03409796 trial data, the computation of VCIEL values showed an improved statistical significance relative to the component values of Vh:Cd and IEL by the within-group paired 2-tailed t test P values from baseline to day 15, particularly at a 10-g gluten challenge dose: Vh:Cd, IEL, VCIEL = .0050, .0031, and .0014, respectively.
Little correlation emerged between baseline values and changes with intervention for Vh:Cd and IEL on an individual patient basis.
The greater accuracy and statistical precision of the VCIEL scale are presumably due to averaging over some of the measurement uncertainty in individual patient and timepoint Vh:Cd and IEL values and creating a composite of different histologic properties, the authors noted.
This study was funded by ImmunogenX, Inc. First author Jack A. Syage is a cofounder and shareholder in ImmunogenX Inc. Dr. Silvester has served on an advisory board for Takeda Pharmaceuticals and has received research funding from Biomedal S.L., Cour Pharmaceuticals, and Glutenostics LLC. Several coauthors disclosed various financial ties to multiple private-sector pharmaceutical and biomedical companies, including ImmunogenX.
, according to a study in Clinical Gastroenterology and Hepatology.
The new morphometric duodenal biopsy mucosal scale joins together villous height-to-crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) — each key CeD histological measures of the small intestine — in a scale called VCIEL.
The authors believe the VCIEL will enable a broader and more accurate measurement of mucosal health in CeD. It will be particularly useful for population analysis in clinical trials and could improve the powering of trial design. “Use of VCIEL may lead to better outcome measures for potential new therapeutic treatments benefiting patients,” wrote Jocelyn A. Silvester, MD, PhD, a pediatrician at Boston Children’s Hospital and an assistant professor at Harvard Medical School, and colleagues.
This chronic enteropathy affects about 1% of the world’s population and requires a lifelong adherence to a gluten-free diet, the authors noted.
The authors pointed to weaknesses in the current quantitative and qualitative ways of measuring gluten-induced mucosal injury on biopsy for CeD. “Morphometry measures the injury continuum for architecture and inflammation, but these are used as separate outcomes,” they wrote. “The original Marsh-Oberhuber [M-O] classifications are rather contrived approaches to assess a biologic continuum, forcing the injury in categorical groups of unclear clinical relevance and where clinically significant changes may occur within one single category.”
Moreover, the quantitation of inflammation relies on binary assessment as normal or increased, which results in histology that is unscorable by M-O if villous atrophy persists without increased IELs, they added.
The Study
In the absence of a broadly accepted single measure of mucosal injury in CeD, the group assessed whether the composite metric could improve statistical precision for assessing histology.
Enter VCIEL, which combines the Vh:Cd and IEL for individual patients with equal weighting by converting each scale to a fraction of their standard deviation and summing the results.
The researchers applied the VCIEL formula in a reanalysis of four clinical gluten-challenge trials and compared the results for Vh:Cd and IEL separately with those for VCIEL for clinical significance (effect size) and statistical significance.
In reanalysis of the ALV003-1021 trial, for example, the researchers observed an effect size and P value (analysis of covariance) of 1.37 and .038 for a delta (difference) value of Vh:Cd 1.17 and .005 for IEL and 1.86 and .004 for VCIEL.
For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding delta results were .76 and .057 for Vh:Cd, .98 and .018 for IEL, and 1.14 and .007 for VCIEL. Comparable improvements with VCIEL over individual Vh:Cd and IEL were observed for other studies, including a nontherapeutic gluten challenge study.
In NCT03409796 trial data, the computation of VCIEL values showed an improved statistical significance relative to the component values of Vh:Cd and IEL by the within-group paired 2-tailed t test P values from baseline to day 15, particularly at a 10-g gluten challenge dose: Vh:Cd, IEL, VCIEL = .0050, .0031, and .0014, respectively.
Little correlation emerged between baseline values and changes with intervention for Vh:Cd and IEL on an individual patient basis.
The greater accuracy and statistical precision of the VCIEL scale are presumably due to averaging over some of the measurement uncertainty in individual patient and timepoint Vh:Cd and IEL values and creating a composite of different histologic properties, the authors noted.
This study was funded by ImmunogenX, Inc. First author Jack A. Syage is a cofounder and shareholder in ImmunogenX Inc. Dr. Silvester has served on an advisory board for Takeda Pharmaceuticals and has received research funding from Biomedal S.L., Cour Pharmaceuticals, and Glutenostics LLC. Several coauthors disclosed various financial ties to multiple private-sector pharmaceutical and biomedical companies, including ImmunogenX.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY