Development of a Radiographic Vertebral Disease Severity Score for Evaluation of Disease Progression in Alkaptonuria
Biochemical/Metabolic and Therapeutics
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Introduction:
Alkaptonuria (AKU) is a rare, autosomal recessive metabolic disorder caused by deficiency of homogentisate 1,2-dioxygenase (HGD), the third enzyme of the tyrosine degradation pathway. Lack of HGD activity leads to accumulation of homogentisic acid (HGA), which oxidizes to benzoquinoneacetic acid, forming melanin-like polymers. Gram quantities of HGA are excreted in the urine leading to darkening upon standing. Circulating HGA binds to collagen, causing the characteristic ochronotic pigmentation in the eyes and ears and destroying connective tissue. The intervertebral discs are particularly affected by this destruction, leading to debilitating spondyloarthropathy due to narrowing of vertebral disc space, calcification of the discs, and trapping of air inside the discs (“vacuum” phenomenon). Nitisinone has long been identified as a potential therapy for AKU as it prevents the formation of HGA by inhibiting 4-hydroxypyruvate dioxygenase, the enzyme producing HGA in the tyrosine catabolic pathway. Evaluation of the efficacy of new therapies requires a system to objectively assess changes in disease progression and correlate with clinical outcomes. Given the irreversibility of the most important findings in AKU, the ability to assess early disease progression is crucial. As spinal involvement is an early finding presenting with pain, stiffness, and loss of range of motion, we developed a radiographic severity score (RSS) as an objective metric of disease progression and correlated with various clinical measurements.
Methods:
The RSS measures progression of spinal disease at 13 levels from C2 to C7 (C-score) and T10 to S1 (L-score). 409 radiographs from 136 participants evaluated between January 2003 and May 2023 were scored. Three different parameters were evaluated: disc space narrowing (characterized as normal, mild, moderate, marked, and fused); presence of calcification; and presence of vacuum phenomenon. All radiographs were randomized and scored by two raters to assess inter-rater reliability. Ten percent of the radiographs were duplicated to assess intra-rater reliability. Participants were then divided into two cohorts, after excluding those receiving nitisinone. The cross-sectional cohort (CSC) contained 122 sets of radiographs, capturing only the latest visit from each participant. The longitudinal cohort (LC) contained 204 sets of radiographs from 59 participants with multiple visits. RSS scores were correlated with age, sex, clinical measurements of disease progression (Schober’s test, 6-minute walk test [6MWT]), and patient-reported outcomes of pain and physical functioning (Pain Disability Index [PDI], Human Activity Profile [HAP], SF-36).
Results:
In both cohorts, the RSS increased over time, showing a strong correlation with age (+1.23 to 1.29 per year, p<0.001). Males displayed more severe scores than women of the same age (+12.72 to 15.06, p<0.001), and spinal disease was more quickly progressive in the lower thoracic/lumbosacral spine than in the cervical spine. After correcting for age and sex, significant correlations were found between the L-score and the Schober’s test (p<0.001 in both cohorts), and the total score correlated with the 6MWT in the cross-sectional cohort (p=0.021). Both cohorts also showed significant correlations between total score and pain (CSC p=0.010, LC p=0.001), physical functioning (CSC p=0.025, LC p=0.034) domains of the SF-36, total PDI (CSC p=0.036, LC p=0.001), and HAP adjusted activity score (CSC p=0.003, LC p=0.025). Intra-rater and inter-reliability were high for the total score (ICC >0.95, p<0.001), validating the reproducibility and reliability of this scoring system. The minimal detectable change with 95% confidence (MDC95) was 2.6 points.
Conclusion:
The RSS is a highly reliable metric to objectively assess the natural history of spinal disease progression in alkaptonuria patients, correlating with age, sex, and several clinical measurements of pain and physical function. Because of its ability to reproducibly capture disease progression, this scoring system is potentially useful to monitor response to therapy.
Alkaptonuria (AKU) is a rare, autosomal recessive metabolic disorder caused by deficiency of homogentisate 1,2-dioxygenase (HGD), the third enzyme of the tyrosine degradation pathway. Lack of HGD activity leads to accumulation of homogentisic acid (HGA), which oxidizes to benzoquinoneacetic acid, forming melanin-like polymers. Gram quantities of HGA are excreted in the urine leading to darkening upon standing. Circulating HGA binds to collagen, causing the characteristic ochronotic pigmentation in the eyes and ears and destroying connective tissue. The intervertebral discs are particularly affected by this destruction, leading to debilitating spondyloarthropathy due to narrowing of vertebral disc space, calcification of the discs, and trapping of air inside the discs (“vacuum” phenomenon). Nitisinone has long been identified as a potential therapy for AKU as it prevents the formation of HGA by inhibiting 4-hydroxypyruvate dioxygenase, the enzyme producing HGA in the tyrosine catabolic pathway. Evaluation of the efficacy of new therapies requires a system to objectively assess changes in disease progression and correlate with clinical outcomes. Given the irreversibility of the most important findings in AKU, the ability to assess early disease progression is crucial. As spinal involvement is an early finding presenting with pain, stiffness, and loss of range of motion, we developed a radiographic severity score (RSS) as an objective metric of disease progression and correlated with various clinical measurements.
Methods:
The RSS measures progression of spinal disease at 13 levels from C2 to C7 (C-score) and T10 to S1 (L-score). 409 radiographs from 136 participants evaluated between January 2003 and May 2023 were scored. Three different parameters were evaluated: disc space narrowing (characterized as normal, mild, moderate, marked, and fused); presence of calcification; and presence of vacuum phenomenon. All radiographs were randomized and scored by two raters to assess inter-rater reliability. Ten percent of the radiographs were duplicated to assess intra-rater reliability. Participants were then divided into two cohorts, after excluding those receiving nitisinone. The cross-sectional cohort (CSC) contained 122 sets of radiographs, capturing only the latest visit from each participant. The longitudinal cohort (LC) contained 204 sets of radiographs from 59 participants with multiple visits. RSS scores were correlated with age, sex, clinical measurements of disease progression (Schober’s test, 6-minute walk test [6MWT]), and patient-reported outcomes of pain and physical functioning (Pain Disability Index [PDI], Human Activity Profile [HAP], SF-36).
Results:
In both cohorts, the RSS increased over time, showing a strong correlation with age (+1.23 to 1.29 per year, p<0.001). Males displayed more severe scores than women of the same age (+12.72 to 15.06, p<0.001), and spinal disease was more quickly progressive in the lower thoracic/lumbosacral spine than in the cervical spine. After correcting for age and sex, significant correlations were found between the L-score and the Schober’s test (p<0.001 in both cohorts), and the total score correlated with the 6MWT in the cross-sectional cohort (p=0.021). Both cohorts also showed significant correlations between total score and pain (CSC p=0.010, LC p=0.001), physical functioning (CSC p=0.025, LC p=0.034) domains of the SF-36, total PDI (CSC p=0.036, LC p=0.001), and HAP adjusted activity score (CSC p=0.003, LC p=0.025). Intra-rater and inter-reliability were high for the total score (ICC >0.95, p<0.001), validating the reproducibility and reliability of this scoring system. The minimal detectable change with 95% confidence (MDC95) was 2.6 points.
Conclusion:
The RSS is a highly reliable metric to objectively assess the natural history of spinal disease progression in alkaptonuria patients, correlating with age, sex, and several clinical measurements of pain and physical function. Because of its ability to reproducibly capture disease progression, this scoring system is potentially useful to monitor response to therapy.