Methotrexate lowers enzyme replacement therapy antibodies
Two girls in Colombia saw motor skills improve with treatment, per case report
Two girls in Colombia with early-onset Pompe disease saw their symptoms improve after methotrexate treatment reduced the levels of antibodies they had developed against enzyme replacement therapy (ERT), according to a case report.
ERT antibodies can cause the therapy to stop working. Methotrexate, a chemotherapy, can work as an immunomodulator by inducing immune tolerance, or making the immune system avoid responding to the body’s own tissues or foreign substances.
“Early diagnosis and timely initiation of enzyme replacement therapy, combined with prophylactic [preventive] immune tolerance induction, may improve clinical outcomes,” the researchers wrote.
The report, “Enzyme replacement therapy and immunotherapy lead to significant functional improvement in two children with Pompe disease: a case report,” was published in the Journal of Medical Case Reports.
In Pompe disease, the body lacks working alpha-glucosidase, an enzyme that helps break down glycogen, a type of stored sugar. Without a functional enzyme, glycogen builds up in the body’s tissues, especially in muscles, causing them to weaken over time.
ERT is main Pompe treatment
The main treatment for Pompe disease is ERT, with a synthetic (lab-made) version of the missing enzyme. This helps to reduce glycogen buildup in tissues. Sometimes, however, the immune system sees the enzyme as a foreign substance and produces antibodies against it, making it less effective.
The two girls described in the report had classic infantile-onset Pompe disease, an early-onset form of the disease. They developed antibodies against Sanofi’s Myozyme (alglucosidase alfa), an ERT approved in the U.S. as Lumyzime to treat all types of Pompe disease.
Both children showed symptoms including hypotonia (low muscle tone) and delays in motor skills. Despite receiving ERT, their symptoms did not ease as expected, and they had notable levels of anti-ERT antibodies in their bloodstreams.
One patient, a 10-month-old girl, was suspected of having early-onset Pompe disease due to her family history and symptoms. She was born healthy, but her brother had died at 15 months from symptoms related to Pompe disease.
Tests confirmed a diagnosis of Pompe disease with disease-causing mutations and low alpha-glucosidase activity. At 12 months, she was started on Myozyme, but after 18 months, her motor skills had not improved, and she had high levels of antibodies against ERT.
Her doctors added methotrexate to her treatment to help reduce these antibodies. After eight months, anti-ERT antibodies were not detected, and her motor skills, measured by a test called the Gross Motor Function Measure 88, improved. She had no side effects related to treatment.
“Motor function assessment showed significant improvement, with the patient able to walk more than ten steps independently, turn around, walk at an accelerated pace, and transition from standing to sitting with support,” the researchers wrote.
The second patient, a 7-year-old girl, was diagnosed with early-onset Pompe disease and started on Myozyme at 12 months. However, by age 5, she experienced frequent falls and grip strength issues. At 6, she had significant motor delays.
She had developed high levels of anti-ERT antibodies. To counteract this, methotrexate was added to her treatment, leading to fewer falls and a decrease in antibody levels after six months. Her motor skills improved, as measured by a test called the Motor Function Measure 32.
The researchers said the cases highlight the importance of regularly checking for the presence of antibodies in patients receiving ERT for Pompe disease. Using specific tests to measure motor function can help doctors monitor how well treatment is working and make necessary adjustments, they wrote.
“Further research is needed to optimize treatment regimens, monitor long-term effects, and address the current limitations of enzyme replacement therapy in Pompe disease,” the researchers wrote.
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