High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy

Poelman, Esther; Hoogeveen‐Westerveld, Marianne; Haan, Marian A. Kroos-de; Hout, J. M. P. van den; Bronsema, Kees J.; Merbel, Nico C. van de; Ploeg, Ans T. van der; Pijnappel, W.W.M. Pim

doi:10.1016/j.jpeds.2017.11.046

Cited by 28 publications

(36 citation statements)

References 29 publications

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“…Another explanation for the differences in individuals' responses to treatment could be the presence of antibodies against the recombinant human acid α-glucosidase. In contrast to patients with classic infantile Pompe disease, [29][30][31] the relationship between antibodies and clinical outcomes in patients with late-onset disease is not clear. Studies so far, containing data for up to 5 years of ERT treatment, have failed to show a clear correlation between antibody titers and patients' individual response to ERT.…”

Section: Discussionmentioning

confidence: 97%

Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease

Harlaar¹,

Hogrel

Perniconi

et al. 2019

Neurology

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ObjectiveTo determine the effects of 10 years of enzyme replacement therapy (ERT) in adult patients with Pompe disease, focusing on individual variability in treatment response. MethodsIn this prospective, multicenter cohort study, we studied 30 patients from the Netherlands and France who had started ERT during the only randomized placebo-controlled clinical trial with ERT in late-onset Pompe disease (NCT00158600) or its extension (NCT00455195) in 2005 to 2008. Main outcomes were walking ability (6-minute walk test [6MWT]), muscle strength (manual muscle testing using Medical Research Council [MRC] grading), and pulmonary function (forced vital capacity [FVC] in the upright and supine positions), assessed at 3-to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixedeffects models for repeated measurements. ResultsMedian follow-up duration on ERT was 9.8 years (interquartile range [IQR] 8.3-10.2 years). At the group level, baseline 6MWT was 49% of predicted (IQR 41%-60%) and had deteriorated by 22.2 percentage points (pp) at the 10-year treatment point (p < 0.001). Baseline FVC upright was 54% of predicted (IQR 47%-68%) and decreased by 11 pp over 10 years (p < 0.001). Effects of ERT on MRC sum score and FVC supine were similar. At the individual level, 93% of patients had initial benefit of ERT. Depending on the outcome measured, 35% to 63% of patients had a secondary decline after ≈3 to 5 years. Still, at 10 years of ERT, 52% had equal or better 6MWT and/or FVC upright compared to baseline. ConclusionsThe majority of patients with Pompe disease benefit from long-term ERT, but many patients experience some secondary decline after ≈3 to 5 years. Individual variation, however, is considerable.Glossary ERT = enzyme replacement therapy; FVC = forced vital capacity; IQR = interquartile range; LOTS = Late-Onset Treatment Study; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MRC = Medical Research Council; M6P = mannose-6-phosphate; pp = percentage points; QMT = quantitative muscle testing; 6MWT = 6-minute walk test.

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Section: Discussionmentioning

confidence: 97%

Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease

Harlaar¹,

Hogrel

Perniconi

et al. 2019

Neurology

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“…This can be explained by the lack of any endogenous GAA protein in CRIM negative patients, which results in the recognition of rhGAA by the immune system and the generation of rhGAA‐specific antibodies. However, most CRIM positive patients with Pompe disease also develop anti‐rhGAA antibodies, likely due to posttranslational differences between the endogenous GAA protein and rhGAA, although on average the antibody titers are lower in CRIM positive patients compared to CRIM negative patients (Kishnani et al, ; Poelman et al, ). Antibodies have the potential to interfere with ERT by binding to rhGAA and thereby neutralizing its activity and/or uptake by muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

et al. 2019

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Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.

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“…Dosing of all patients receiving 20 mg/kg eow was increased to 40 mg/kg/week somewhere between 2009 and 2014, due to clinical deterioration. In 2012, immunomodulation with rituximab (RTX), methotrexate (MTX) and intravenous immunoglobulins (IVIG) in an ERT-naïve setting was initiated in newly diagnosed patients older than 2 months of age at the time of diagnosis (see for details 25 ). Antibiotic prophylaxis was given to prevent (respiratory) infections.…”

Section: Patients and Treatmentmentioning

confidence: 99%

Effects of higher and more frequent dosing of alglucosidase alfa and immunomodulation on long‐term clinical outcome of classic infantile Pompe patients

Poelman

Dorpel

Hoogeveen‐Westerveld

et al. 2020

J of Inher Metab Disea

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The aim of this study was to compare the long-term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/ kg/week. Five patients were cross-reactive immunologic material (CRIM)-negative, two in the 20 mg, three in the 40 mg group. We compared (ventilatorfree) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)-naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator-free survival was 50% and 92%. Both CRIM-negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age

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High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy

Abstract: Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.

Cited by 28 publications

References 29 publications

Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease

Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

Effects of higher and more frequent dosing of alglucosidase alfa and immunomodulation on long‐term clinical outcome of classic infantile Pompe patients

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