An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease

Zoheb B. Kazi, Ankit K. Desai, R. Bradley Troxler, David Kronn, Seymour Packman, Marta Sabbadini, William B. Rizzo, Katalin Scherer, Omar Abdul-Rahman, Pranoot Tanpaiboon, Sheela Nampoothiri, Neerja Gupta, Annette Feigenbaum, Dmitriy M. Niyazov, Langston Sherry, Reeval Segel, Alison McVie-Wylie, Crystal Sung, Alexandra M. Joseph, Susan RichardsPriya S. Kishnani

Research output: Contribution to journalArticle

3 Scopus citations


Purpose: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients. Methods: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone. Results: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7–13.5 months) had a median last titer of 150 (range, 0–51,200) at median rhGAA duration ~83 weeks (range, 36–122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200–409,600), 7/37 SIT (12,800–51,000), and 23/37 LT (200–12,800) among comparators. Conclusion: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.

Original languageEnglish (US)
JournalGenetics in Medicine
Publication statusAccepted/In press - Jan 1 2018



  • alglucosidase alfa
  • antidrug antibodies
  • methotrexate
  • Pompe disease
  • prophylactic immune tolerance induction

ASJC Scopus subject areas

  • Genetics(clinical)

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