Radiological evolution of spinal disease in alkaptonuria and the effect of nitisinone

Abstract

Objectives: Ochronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking.

Methods: Patients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points.

Results: At baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment.

Conclusion: The present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time.

Trial registration number: NCT01916382.

Keywords: Arthritis; Osteoarthritis; Treatment.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Examples of radiographic features in the cervical (A), thoracic (B) and lumbosacral (C) regions of the spine in woman in her 60s (A), man in his 60s (B) and man in his 50s (C) with alkaptonuria: narrowing of the intervertebral space (black full arrow), soft tissue calcifications (black dashed arrow), vacuum phenomena (white full arrow), osteophytes and/or hyperostosis (white dashed arrow) and spinal fusion (black dash dot arrow).

Figure 2

Correlations between cumulative scores (cervical+thoracic+lumbosacral) for each of the five radiographic features, that is, narrowing of the intervertebral space (top left), soft tissue calcifications (bottom left), vacuum phenomena (top centre), osteophytes and/or hyperostosis (bottom centre) and spinal fusion (top right) and age in the spine of patients with alkaptonuria as well as between age and the sum of scoring in all five radiographic features (bottom right). The squared Pearson correlation coefficient (r2) and respective p value are showed under each of the panels.

Figure 3

Radiographic scores (mean, SE), that is, narrowing of the intervertebral space (top left), soft tissue calcifications (top right), vacuum phenomena (mid left), osteophytes and/or hyperostosis (mid right), spinal fusion (bottom left) and sum of all features in all spine segments (bottom right) in 69 (N=69) patients with alkaptonuria on nitisinone 10 mg/day (black circles, full line) and in 69 (N=69) untreated patients during 48 months.

Figure 4

Change in sum of scores (mean, SE) for all five radiographic features (narrowing of the intervertebral space+soft tissue calcifications+vacuum phenomena+osteophytes and/or hyperostosis+spinal fusion) in the cervical (top), thoracic (centre) and lumbosacral (bottom) regions of the spine in 69 (N=69) patients with alkaptonuria on nitisinone 10 mg/day (black circles, full line) and in 69 untreated patients from the baseline (Month 0) to Month 48. P value (Mann-Whitney U test) denotes treatment versus non-treatment difference in increments (Month 48 minus Month 0).