Reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy: Analysis of data from the United Kingdom National Alkaptonuria Centre

Abstract

Background Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression. Methods Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V‐1 (pre‐baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24‐hour urine samples were collected for measurement of HGA. Results There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V‐1 visit. Photographs of patients show increase in eye pigment between V‐1 and V0, followed by decrease post‐nitisinone at V1, V2, and V3. Ear and combined ochronosis semiquantitative scoring showed an increase between V‐1 and V0 (P < .01), followed by a decrease at V1, V2, and V3, in the VAR group (P < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease (P < .05). Conclusions Nitisinone decreases HGA and partially reverses ochronosis.

Characterising the arthroplasty in spondyloarthropathy in a large cohort of eighty‐seven patients with alkaptonuria

“…Ochronosis scores were strongly directly related to joint replacements, similar to those of PAIN, PETCT and SPOND, providing a direct relationship between ochronosis and joint disease in AKU. Despite the profound decrease in serum and urine HGA, by 87 and 93.8% respectively, 6,7,20 and significant reversal of ochronosis progression in the eyes and ears, 21 neither SPOND nor arthroplasty, were significantly modified by nitisinone. A larger number of patient/years may be needed to determine if there is a significant change on joint features, including arthroplasty.…”

“…Arrest of ochronotic pigment formation could stabilise cartilage damage in AKU, and minimise progression to end‐stage joint failure. A recent report showed reversal of ochronosis in the ear and eye in human AKU, and this reversal is also demonstrated for internal ochronosis, it could bring hope to those with advanced AKU disease 21 . However, less is known about the effect of nitisinone on joint replacements and other surgical procedures of joints and spine, the focus of the present analysis.…”

“…A larger number of patient/years may be needed to determine if there is a significant change on joint features, including arthroplasty. Ochronosis reversal in the eye and ear has been described recently and a mechanism is lacking; it is not unlikely to be due to a change in the chemical equilibrium between the circulating HGA and ochronotic pigment 21 . A decrease in HGA may allow HGA to leach out of the pigment leading to ochronosis reversal.…”

“…A recent report showed reversal of ochronosis in the ear and eye in human AKU, and this reversal is also demonstrated for internal ochronosis, it could bring hope to those with advanced AKU disease. 21 However, less is known about the effect of nitisinone on joint replacements and other surgical procedures of joints and spine, the focus of the present analysis. A previous study examining low dose nitisinone therapy in 40 AKU patients over 3 years did not described any effect of nitisinone on joint replacements, having found just two incident joint replacements during the study.…”

Characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients

“…The arrest of ochronotic pigment formation could stabilize cartilage damage in AKU. Recent observations in human AKU suggest that ochronosis, visible externally in the ear and eyes, may reverse significantly postnitisinone, bringing hope to those with advanced AKU disease 14 . However, less is known about the effect of nitisinone on spondyloarthropathy.…”