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. 2020 Dec 8;58(1):89-99.
doi: 10.1002/jmd2.12190. eCollection 2021 Mar.

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I

Troy C Lund  1 , Terence M Doherty  2 , Julie B Eisengart  1 , Rebecca L Freese  3 , Kyle D Rudser  4 , Ellen B Fung  5 , Bradley S Miller  1 , Klane K White  6 , Paul J Orchard  1 , Chester B Whitley  1 , Lynda E Polgreen  2
Affiliations

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I

Troy C Lund et al. JIMD Rep. .

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.

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Conflict of interest statement

Dr T. C. L. receives research support from Sanofi‐Genzyme. Dr J. B. E. has received honoraria, consulting fees, and/or research support from ArmaGen, JCR pharmaceuticals, Orchard Therapeutics, Bluebird Bio, Shire/Takeda, and Sanofi‐Genzyme. Ms R. L. F. declares that she has no conflict of interest. Dr K. D. R. declares that he has no conflict of interest. Dr E. B. F. is a consultant for BioMarin Pharmaceuticals and Ascendis. Dr B. S. M. is a consultant for AbbVie, Ascendis, Ferring, Novo Nordisk, Pfizer, Sandoz, and Versartis and has received research support from Alexion, Ascendis, Endo Pharmaceuticals, Genentech, Genzyme, Novo Nordisk, Opko, Sandoz, Sangamo, Shire, Tolmar, and Versartis. Dr K. K. W. is a consultant for BioMarin Pharmaceuticals, has received honoraria from BioMarin Pharmaceuticals, Sanofi‐Genzyme, has grant funding from BioMarin Pharmaceuticals and Ultragenyx, and receives royalties from UpToDate.com. Dr C. B. W. is a consultant for Sanofi‐Genzyme. Dr P. J. O. receives research and clinical trial support from Sanofi‐Genzyme, Horizon, Magenta, and Bluebird Bio. Dr L. E. P. is a speaker and consultant for Sanofi‐Genzyme, has received research support from Sanofi‐Genzyme, Shire, BioMarin, and Pfizer‐Therachon, and is a consultant for Sangamo, Immusoft, Pfizer‐Therachon, and BioMarin.

Figures

FIGURE 1
FIGURE 1
Change in joint range of motion (ROM) summary score (sum of bilateral shoulder flexion, elbow, and knee extension), height Z‐score, Reimers migration index (RMI), and Tonnis angle over time. Filled circles and solid lines = MPS IH; open circles and dotted lines = MPS IA
FIGURE 2
FIGURE 2
Inflammatory, A‐C, and bone, D‐F, biomarker concentrations in mucopolysaccharidosis type I (MPS I) compared to healthy controls. Mean ± SEM is shown. P ‐ values adjusted for BMI Z‐score, A‐C, or age, D‐F. *P < .05; **P < .001. DPD, urine deoxypyridinolines; IL‐1β, interleukin‐1β; IL‐6, plasma interleukin‐6; OCN, plasma osteocalcin; PYD, urine pyridinolines; TNF‐α, tumor necrosis factor‐α
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