High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient

Abstract

Alglucosidase alfa (rhGAA) has altered the course of an otherwise fatal outcome in classic infantile Pompe disease (IPD), which presents with cardiomyopathy and severe musculoskeletal involvement. However, the response to therapy is determined by several factors including the development of high and sustained antibody titers (HSAT) to rhGAA. Cross-reactive immunologic material (CRIM) negative patients are at the highest risk for development of HSAT. Immune tolerance induction (ITI) with methotrexate, rituximab, and intravenous immunoglobulin (IVIG) has been largely successful in preventing the immune response and in achieving tolerance when done in conjunction with enzyme replacement therapy (ERT) initiation. Reducing antibody titers in cases with an entrenched immune response remains a challenge in the field despite the use of multiple immunomodulatory agents. Success has been shown with addition of bortezomib to the ITI regimen, yet the prolonged course and potential risks with the use of such agents’ demands caution. We present here a 7-year-old CRIM-negative IPD patient who was not successfully tolerized by an ITI regimen with rituximab, methotrexate, and IVIG due to intolerability to the regimen and recurrent infections. She went on to develop HSAT, with significant clinical decline, loss of all motor abilities, and a fragile medical state, which made it challenging to institute the bortezomib based regimen to reduce HSAT. She had severe developmental delay, respiratory failure with invasive ventilation and tracheostomy, persistent hypotonia, ptosis of eyelids, diffuse severe osteopenia, contractures, and was completely G-tube fed. As a rescue mechanism, we treated her with high dose and high frequency IVIG in an attempt to reduce rhGAA IgG antibody titers (antibody titers; titers). Her titers saw a steady decline on weekly IVIG doses at 1 g/kg for 20 weeks. Subsequently when the IVIG regimen was altered to 1 g/kg every month, rising titers were detected and therefore the regimen was changed to a biweekly regimen. High dose IVIG resulted in an eightfold decrease in antibody titers. Clinically, she showed improvement with partial recovery of previously lost motor abilities, especially hand movements and better head and neck control than before. The regimen was safely tolerated with no hospitalizations. The effectiveness of IVIG as a single agent, in this case with multiple comorbidities and fragile clinical status, was lifesaving and may represent an effective, perhaps lifesaving rescue approach to reduce antibody titers.

Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel

“…Anecdotal reports have been made on the use of plasma exchange to remove pathogenic antibodies and immune complexes from plasma and high-dose IVIG (1–3 g/kg/week) in patients with adverse reactions to other drugs, but with modest results, and in patients with low antibody titers involving, in the case of plasma exchange, additional risks related to the procedure [ 52 , 53 ].…”

“…Binding to the neonatal Fc receptor (FcRn) which is responsible for recycling of antibodies thus downregulating antibody responses [ 53 , 57 , 58 ]…”

“…Bortezomib Proteasome inhibition: blocks protein recycle and production of antibodies in plasma cells a [55,56] Peripheral neuropathy, anemia, neutropenia, thrombocytopenia, gastrointestinal and cardiac side effects [23] IVIG Binding to the neonatal Fc receptor (FcRn) which is responsible for recycling of antibodies thus downregulating antibody responses [53,57,58] Passive immunity during the period of immune suppression due to other drugs (specially rituximab) [23] Infusion-associated reactions [59] Methotrexate Inhibits folic acid metabolism (which blocks de novo DNA synthesis), thus eliminating dividing B and T cells. Low dose: Induces regulatory B cells rather than cell depletion [60,61] Bone marrow and gastrointestinal toxicities, rarely acute pneumonitis, pulmonary fibrosis and renal function impairment [12,62] Mycophenolate mofetil Inhibition of proliferative responses of T and B lymphocytes [12] Leukopenia, anemia and thrombocytopenia Rapamycin Mammalian target of rapamycin (mTOR), which inhibits cell survival and proliferation of B and T lymphocytes, but selectively promotes regulatory T -Treg -cells b [63][64][65][66][67] Rituximab Monoclonal antibody against CD20 molecule expressed on B cells [12] Infusion-associated reactions, lymphocytopenia, progressive multifocal leukoencephalopathy [62] rate, and concentration), monitoring of vital signs, symptom-specific medical intervention (e.g.…”

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

“…reported the efficacy of ITI using bortezomib, rituximab, rapamycin, and IVIg in one CRIM-positive and two CRIM-negative IOPD patients ( 13 ). Using weekly IVIg doses at 1 g/kg as a single agent for 20 weeks has also been effective ( 18 ). Our study contributes to the evidence by showcasing the effectiveness of a combined regimen of bortezomib, rituximab, methotrexate, and IVIg over six months, which sustained effects for up to 4.5 years.…”

“…For CRIM-negative IOPD patients, initiating immune tolerance induction (ITI) therapy concurrent with ERT has become the standard of care, aiming to prevent ADA formation and minimize their negative impact on treatment ( 13 , 15 ). Several immunomodulatory agents, including rituximab, methotrexate, intravenous immunoglobulin (IVIg), and omalizumab, have been tested as monotherapy or combined, achieving varying degrees of success ( 15 – 18 ). Consequently, prophylactic immunomodulation prior to ERT initiation is commonly used in CRIM-positive IOPD patients at high risk of ADA development or those with indeterminate CRIM status requiring urgent treatment ( 10 , 19 ).…”