Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I

Troy C. Lund; Terence M. Doherty; Julie B. Eisengart; Rebecca L. Freese; Kyle D. Rudser; Ellen B. Fung; Bradley S. Miller; Klane K. White; Paul J. Orchard; Chester B. Whitley; Lynda E. Polgreen

doi:10.1002/jmd2.12190

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I

Troy C. Lund, Terence M. Doherty, Julie B. Eisengart, Rebecca L. Freese, Kyle D. Rudser, Ellen B. Fung, Bradley S. Miller, Klane K. White, Paul J. Orchard, Chester B. Whitley, Lynda E. Polgreen

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Background: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease.

Methods: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes.

Results: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1β, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; P < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; P = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; P = .037).

Conclusions: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.

Original language	English (US)
Pages (from-to)	89-99
Number of pages	11
Journal	JIMD Reports
Volume	58
Issue number	1
DOIs	https://doi.org/10.1002/jmd2.12190
State	Published - Mar 1 2021

Bibliographical note

Funding Information:
The authors thank the patients and their families for their participation in these studies, and the study personnel at participating centers, including Jane Kennedy, Eva Villa-Lopez, Angel Zozobrado, and Ashley Weisenburger. National Institute of Arthritis and Musculoskeletal and Skin Diseases K23AR057789; National Institute of Neurological Disorders and Stroke U54NS065768; National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) UL1TR001881, UL1TR000114, UL1TR002484, and UL1RR024131; Sanofi-Genzyme 21493-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH National Center for Advancing Translational Sciences.

Publisher Copyright:
© 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.

Keywords

Hurler
Scheie
biomarker
bone
cytokines
inflammation
mucopolysaccharidosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/jmd2.12190

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@article{eb828f0a80c94eeb8cba7d6b7949208b,

title = "Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I",

abstract = "Background: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease.Methods: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes.Results: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1β, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; P < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; P = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; P = .037). Conclusions: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.",

keywords = "Hurler, Scheie, biomarker, bone, cytokines, inflammation, mucopolysaccharidosis",

author = "Lund, {Troy C.} and Doherty, {Terence M.} and Eisengart, {Julie B.} and Freese, {Rebecca L.} and Rudser, {Kyle D.} and Fung, {Ellen B.} and Miller, {Bradley S.} and White, {Klane K.} and Orchard, {Paul J.} and Whitley, {Chester B.} and Polgreen, {Lynda E.}",

note = "Funding Information: The authors thank the patients and their families for their participation in these studies, and the study personnel at participating centers, including Jane Kennedy, Eva Villa-Lopez, Angel Zozobrado, and Ashley Weisenburger. National Institute of Arthritis and Musculoskeletal and Skin Diseases K23AR057789; National Institute of Neurological Disorders and Stroke U54NS065768; National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) UL1TR001881, UL1TR000114, UL1TR002484, and UL1RR024131; Sanofi-Genzyme 21493-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH National Center for Advancing Translational Sciences. Publisher Copyright: {\textcopyright} 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.",

year = "2021",

month = mar,

day = "1",

doi = "10.1002/jmd2.12190",

language = "English (US)",

volume = "58",

pages = "89--99",

journal = "JIMD Reports",

issn = "2192-8304",

publisher = "Springer Berlin",

number = "1",

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TY - JOUR

T1 - Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I

AU - Lund, Troy C.

AU - Doherty, Terence M.

AU - Eisengart, Julie B.

AU - Freese, Rebecca L.

AU - Rudser, Kyle D.

AU - Fung, Ellen B.

AU - Miller, Bradley S.

AU - White, Klane K.

AU - Orchard, Paul J.

AU - Whitley, Chester B.

AU - Polgreen, Lynda E.

N1 - Funding Information: The authors thank the patients and their families for their participation in these studies, and the study personnel at participating centers, including Jane Kennedy, Eva Villa-Lopez, Angel Zozobrado, and Ashley Weisenburger. National Institute of Arthritis and Musculoskeletal and Skin Diseases K23AR057789; National Institute of Neurological Disorders and Stroke U54NS065768; National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) UL1TR001881, UL1TR000114, UL1TR002484, and UL1RR024131; Sanofi-Genzyme 21493-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH National Center for Advancing Translational Sciences. Publisher Copyright: © 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Background: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease.Methods: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes.Results: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1β, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; P < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; P = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; P = .037). Conclusions: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.

AB - Background: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease.Methods: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes.Results: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1β, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; P < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; P = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; P = .037). Conclusions: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.

KW - Hurler

KW - Scheie

KW - biomarker

KW - bone

KW - cytokines

KW - inflammation

KW - mucopolysaccharidosis

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DO - 10.1002/jmd2.12190

M3 - Article

C2 - 33728251

AN - SCOPUS:85102237412

SN - 2192-8304

VL - 58

SP - 89

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JO - JIMD Reports

JF - JIMD Reports

IS - 1

ER -

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I

Abstract

Bibliographical note

Keywords

UN SDGs

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