title: B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.
abstract: OBJECTIVE
  To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes.
  
  
  METHODS
  Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly.
  
  
  RESULTS
  Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates.
  
  
  CONCLUSIONS
  B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Elder
authors.forename: Sushrusha
authors.initials: S
authors.lastname: Nayak
authors.forename: Shelley W
authors.initials: SW
authors.lastname: Collins
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Lawson
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Kelley
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.forename: Renee F
authors.initials: RF
authors.lastname: Modica
authors.forename: Judy
authors.initials: J
authors.lastname: Lew
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lawrence
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D015703:Antigens, CD / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D056947:Enzyme Replacement Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069283:Rituximab; D020123:Sirolimus / Q000627:therapeutic use*; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D001323:Autoantibodies; D015415:Biomarkers; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000069283:Rituximab; C509951:GAA protein, human; D000520:alpha-Glucosidases; D009173:Mycophenolic Acid; D020123:Sirolimus
keywords: Ab; Acid alpha-glucosidase; Antibody; CRIM; Cross-reactive immunologic material; ERT; Enzyme replacement therapy; GAA; IV; IVIG; Intravenous; Intravenous immunoglobulin; LVMI; Left ventricular mass index