Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy

Langereis, Eveline J.; Vlies, Naomi van; Church, Heather J.; Geskus, Ronald B.; Hollak, Carla E. M.; Jones, Simon A.; Kulik, Wim; Lenthe, Henk van; Mercer, Jean; Schreider, Lena; Tylee, Karen; Wagemans, Tom; Wijburg, Frits A.; Bigger, Brian

doi:10.1016/j.ymgme.2014.10.012

Cited by 52 publications

(34 citation statements)

References 45 publications

(80 reference statements)

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“…These biomarkers have been validated previously and are the most responsive to treatment. 10,11 All data were tabulated and descriptive statistics used to demonstrate the COM scores of each individual eye and also of each individual patient for the 2011 visit compared to the 2015/2016 visit. All statistics were performed on Microsoft Excel (Version 14.0, Microsoft Corporation) and SPSS Version 22.0 (IBM, New York, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

Objective Quantification of Changes in Corneal Clouding Over Time in Patients With Mucopolysaccharidosis

Javed

Aslam

Jones

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Javed A, Aslam T, Jones SA, Ashworth J. Objective quantification of changes in corneal clouding over time in patients with mucopolysaccharidosis. Invest Ophthalmol Vis Sci. 2017;58:954-958. DOI:10.1167/ iovs.16-20647 PURPOSE. We determine objective changes in corneal opacification levels over time in patients with mucopolysaccharidoses (MPS) treated with enzyme replacement therapy or hematopoietic stem cell transplant. A prospective cohort study was done of 9 patients with MPS I (Hurler) or VI (Maroteaux-Lamy).METHODS. Quantification of corneal clouding using the Iris camera and full ophthalmic examination, including subjective assessment of corneal clouding, was done in 2011 and repeated in 2015/2016. Patients also had assessment of biomarkers, including dermatan sulfate/chondroitin sulfate (DS/CS) ratio. Change in corneal opacification were measured by Iris camera corneal opacification measure (COM) score during a mean of 60 months followup. RESULTS.A total of 5/17 (29%) eyes had a deterioration in COM score, indicating increased corneal clouding. There was no significant change in COM score in 10/17 (59%) patient eyes. One patient (2/17 eyes) demonstrated significant improvement in corneal clarity and this was associated with improved biomarker levels.CONCLUSIONS. Assessment of COM scores using the Iris camera are an objective means of monitoring corneal opacification over time in patients with MPS. Corneal opacification may potentially be reversed with intensive treatment demonstrated by impact on biomarkers.Keywords: mucopolysaccharidoses, paediatric ophthalmology, metabolic medicine T he mucopolysaccharidoses (MPS) are a group of rare metabolic diseases characterized by defects of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Glycosaminoglycan deposition in multiple tissues and organs results in a wide range of systemic manifestations, including dysmorphic facial features, vision and hearing impairment, cardiorespiratory problems, joint and bone diseases, neurologic problems, and intellectual impairment. Corneal opacification is an early clinical feature in several of the MPS subtypes (MPSI Hurler and Hurler-Scheie, MPSIVA Morquio, MPSVI Maroteaux-Lamy, MPSVII Sly), and can result in significant visual impairment.1 In addition, complications, such as retinopathy, glaucoma, and optic neuropathy, may contribute to visual loss in patients with MPS. Current treatment options for MPS include enzyme replacement therapy (ERT), which is available for MPS I, II, IVA, and VI; and hematopoietic stem cell transplantation (HSCT), which is useful for selected patients with MPS types I and VI.1,2 The untreated clinical course of corneal clouding in MPS is thought to be one of gradual deterioration, but the extent and speed of deterioration have not been documented. Enzyme replacement therapy is known to be effective in improving the systemic manifestations of MPS in types I, II, IVA, and VI by improving respiratory function and stamina, and improving quality of life.2...

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Section: Methodsmentioning

confidence: 99%

Objective Quantification of Changes in Corneal Clouding Over Time in Patients With Mucopolysaccharidosis

Javed

Aslam

Jones

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…These results suggest that for patients treated with laronidase without immune tolerance induction, the risk/benefit profile over the duration of treatment is acceptable. A recent publication evaluating cross-sectional data from 2 prospective open-label studies showed that a persistent antibody response might be related to an impaired biomarker response, but as in the meta-analysis, there was no correlation with clinical outcomes [20]. On the other hand, data from sleep oximetry studies conducted in 61 patients with MPS I (44 with severe, and 17 with attenuated disease) showed a higher rate of sleep apnea/airway obstruction and need for intervention in patients receiving ERT who had a strong inhibitory antibody response, suggesting a potential benefit of immune tolerance [24].…”

Section: Discussionmentioning

confidence: 86%

Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I

Giugliani

Vieira

Carvalho

et al. 2017

Molecular Genetics and Metabolism Reports

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Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058–0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. Clinical Trial Registration: NCT00741338.

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“…No statistical significance could be demonstrated however, due small cohort size [12]. More recently, Langereis et al confirmed the impact of antibodies in MPS-I patients during long term treatment (median 2.3 years, range 2e92 months) demonstrating a more robust biochemical response in antibody negative patients as compared to antibody positive patients [65]. In constitutive, neuronopathic MPS-I, (Hurler), allogeneic haematopoietic stem cell transplantation (HSCT) remains the treatment of choice.…”

Section: Mps-imentioning

confidence: 99%