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.
Bibliographical noteFunding 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.
© 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.
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