Effects of immunomodulation in classic infantile Pompe patients with high antibody titers

Poelman, Esther; Hoogeveen‐Westerveld, Marianne; Hout, J. M. P. van den; Bredius, Robbert G. M.; Lankester, Arjan C.; Kamphuis, S. S. M.; Pijnappel, W.W.M. Pim; Ploeg, Ans T. van der

doi:10.1186/s13023-019-1039-z

Cited by 25 publications

(28 citation statements)

References 32 publications

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“…Symptoms in other tissues and organs also occur including in smooth muscle, visceral organs, and, in the classic infantile form, the central nervous system. Enzyme replacement therapy with recombinant human GAA is available and is often applied in combination with immunomodulation in classic infantile cases to reduce the chance of antibody formation [10][11][12][13]. Early diagnosis including phenotype prediction is required to optimize counseling and to ensure a timely start of treatment.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic diagnosis of Pompe disease: lessons from 28 years of experience

et al. 2020

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Pompe disease is a lysosomal and neuromuscular disorder caused by deficiency of acid alpha-glucosidase (GAA), and causes classic infantile, childhood onset, or adulthood onset phenotypes. The biochemical diagnosis is based on GAA activity assays in dried blood spots, leukocytes, or fibroblasts. Diagnosis can be complicated by the existence of pseudodeficiencies, i.e., GAA variants that lower GAA activity but do not cause Pompe disease. A large-scale comparison between these assays for patient samples, including exceptions and borderline cases, along with clinical diagnoses has not been reported so far. Here we analyzed GAA activity in a total of 1709 diagnostic cases over the past 28 years using a total of 2591 analyses and we confirmed the clinical diagnosis in 174 patients. We compared the following assays: leukocytes using glycogen or 4MUG as substrate, fibroblasts using 4MUG as substrate, and dried blood spots using 4MUG as substrate. In 794 individuals, two or more assays were performed. We found that phenotypes could only be distinguished using fibroblasts with 4MUG as substrate. Pseudodeficiencies caused by the GAA2 allele could be ruled out using 4MUG rather than glycogen as substrate in leukocytes or fibroblasts. The Asian pseudodeficiency could only be ruled out in fibroblasts using 4MUG as substrate. We conclude that fibroblasts using 4MUG as substrate provides the most reliable assay for biochemical diagnosis and can serve to validate results from leukocytes or dried blood spots.

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Section: Introductionmentioning

confidence: 99%

Enzymatic diagnosis of Pompe disease: lessons from 28 years of experience

et al. 2020

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“…Most ITI protocols require long term, frequent (>3 times a week) administration of the recombinant protein and are still only successful in 60-70% of cases for hemophilia A and only 30% of cases for hemophilia B [19,30]. In Pompe disease, ITI has been tried with intensive immune-modulatory protocols (including rituximab, methotrexate, bortezomib and intraveneus immunoglobulines) resulting in a steady decrease in iADAs and improvement of therapeutic effectiveness, but full tolerization was not achieved [17,18]. This is in accordance with the findings from Lenders et al in FD patients who underwent kidney or heart transplantation (and were thus treated with immunosuppressive therapy).…”

Section: Discussionmentioning

confidence: 99%

“…Experience in other disorders in which treatment with recombinant proteins is hampered by iADA formation (e.g., hemophilia, Pompe disease and MPS1) [13][14][15][16], shows that once iADAs occur, they tend to persist despite treatment with immunosuppressants or tolerization protocols (e.g., immune tolerance is hard to achieve) [17][18][19][20]. Therefore, it is important to develop protocols that can prevent or treat iADAs.…”

Section: Introductionmentioning

confidence: 99%

Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

Veen

Vlietstra²,

Dussen

et al. 2020

IJMS

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Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.

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“…Although there are different strategies to tolerize Pompe disease patients that vary vis-à-vis drug combinations, concentrations, and duration [59][60][61][62], they all include rituximab, a CD20 (B cell surface antigen)-directed cytolytic antibody. In a recently reported highly efficacious protocol, high-risk patients who were all less than 3 months old were put on a short-term regimen of rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in conjunction with concomitant acid α-glucosidase therapy [63].…”

Section: Addressing Clinical Immunogenicitymentioning

confidence: 99%