Abstract
Hypophosphatasia (HPP) is the heritable metabolic disease characterized by impaired skeletal mineralization due to low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. Although HPP during growth often manifests with distinctive radiographic skeletal features, no validated method was available to quantify them, including changes over time. We created the Radiographic Global Impression of Change (RGI-C) scale to assess changes in the skeletal burden of pediatric HPP. Site-specific pairs of radiographs of newborns, infants, and children with HPP from three clinical studies of asfotase alfa, an enzyme replacement therapy for HPP, were obtained at baseline and during treatment. Each pair was scored by three pediatric radiologists ("raters"), with nine raters across the three studies. Intrarater and interrater agreement was determined by weighted Kappa coefficients. Interrater reliability was assessed using intraclass correlation coefficients (ICCs) and by two-way random effects analysis of variance (ANOVA) and a mixed-model repeated measures ANOVA. Pearson correlation coefficients evaluated relationships of the RGI-C to the Rickets Severity Scale (RSS), Pediatric Outcomes Data Collection Instrument Global Function Parent Normative Score, Childhood Health Assessment Questionnaire Disability Index, 6-Minute Walk Test percent predicted, and Z-score for height in patients aged 6 to 12 years at baseline. Eighty-nine percent (8/9) of raters showed substantial or almost perfect intrarater agreement of sequential RGI-C scores (weighted Kappa coefficients, 0.72 to 0.93) and moderate or substantial interrater agreement (weighted Kappa coefficients, 0.53 to 0.71) in patients aged 0 to 12 years at baseline. Moderate-to-good interrater reliability was observed (ICC, 0.57 to 0.65). RGI-C scores were significantly (p ≤ 0.0065) correlated with the RSS and with measures of global function, disability, endurance, and growth in the patients aged 6 to 12 years at baseline. Thus, the RGI-C is valid and reliable for detecting clinically important changes in skeletal manifestations of severe HPP in newborns, infants, and children, including during asfotase alfa treatment. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Highlights
Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism characterized enzymatically by low activity of the tissuenonspecific isoenzyme of alkaline phosphatase (TNSALP) and caused by loss-of-function mutation(s) in ALPL (TNSALP), the gene that encodes this cell-surface phosphohydrolase.[1,2,3] To date, more than 340 such mutations, primarily missense defects, have been identified in patients with HPP.[4]
In 2000, a Rickets Severity Scale (RSS) was developed to assess radiographic features in the wrists and knees of patients with nutritional rickets.[8]. Because assessing radiographic features is important for patients with skeletal manifestations of HPP, a scale that encompasses the characteristic changes of HPP seemed necessary to best evaluate therapeutic responses.[7]
Based on specified radiographs of affected newborns, infants, and children, we developed the Radiographic Global Impression of Change (RGI-C) scale to address the unmet need to quantify changes in key skeletal manifestations of pediatric HPP
Summary
Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism characterized enzymatically by low activity of the tissuenonspecific isoenzyme of alkaline phosphatase (TNSALP) and caused by loss-of-function mutation(s) in ALPL (TNSALP), the gene that encodes this cell-surface phosphohydrolase.[1,2,3] To date, more than 340 such mutations, primarily missense defects, have been identified in patients with HPP.[4]. HPP is characterized by remarkably broad-ranging severity and can be lethal in utero or not manifest until late adult life.[5] In HPP, extracellular accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization, often leads to rickets or osteomalacia.[6] In affected newborns, infants, and children, HPP can cause limb deformity, muscle weakness, musculoskeletal pain, fractures, poor growth, and premature loss of deciduous teeth.[3,6] When HPP presents during growth, radiography can uncover skeletal features that are pathognomonic.[1,3,7]. We describe and validate the Radiographic Global Impression of Change (RGI-C) scale as a tool for scoring changes over time in key radiographic features of HPP in pediatric patients. Our evaluation of the RGI-C measured agreement and reliability of scores given by multiple raters to select radiographs, and we determined the correlation of the scores to other outcome measures using data from three recently completed clinical studies of asfotase alfa treatment (Strensiq®; Alexion Pharmaceuticals, Inc., New Haven, CT, USA), an enzyme replacement therapy approved multinationally in 2015, typically for the treatment of pediatric-onset HPP.[9,10,11]
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