Use of methotrexate may make Pompe treatment more effective, per study
Immunosuppressive drug showed benefits in people with 2 disease types
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Using a short course of low-dose methotrexate, an immunosuppressive agent, alongside enzyme replacement therapy (ERT) in people with Pompe disease may help prevent the formation of antibodies that can reduce treatment effectiveness.
That’s the key finding of a new study by Duke University researchers, who found that this regimen appeared to decrease immune activation in people with infantile-onset Pompe (IOPD) while generating immune tolerance in individuals with late-onset Pompe (LOPD). The team noted that all but three patients across both groups showed no signs of developing high anti-ERT antibody levels after the use of this treatment.
Other strategies have been used to reduce this immune response in patients, the researchers noted, but these have had some negative effects.
Here, “a novel approach using transient low-dose methotrexate (TLD-MTX) was implemented and proved successful in this [patient] population,” the team wrote.
According to the researchers, “this approach may offer a more manageable and widely available option for controlling … antibody production in Pompe patients, with potentially fewer … side effects.”
The study, “Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in Infantile- vs. late-onset Pompe disease patients,” was published in the journal Frontiers in Immunology.
In Pompe, an inherited deficiency of the enzyme acid alpha-glucosidase (GAA) prevents the breakdown of glycogen, a stored form of sugar. Without GAA, glycogen accumulates in muscle tissue, resulting in progressive muscle weakness.
The disease has two main forms: IOPD is the most severe form and emerges within the first few months of life, while LOPD progresses more slowly, with symptoms beginning anywhere from infancy to late adulthood. In both types, ERT — treatment with a lab-made version of human GAA — has changed the course of Pompe by slowing or preventing the toxic glycogen buildup in muscles.
Still, some patients develop high and sustained levels of antibodies against ERT, which reduces its effectiveness.
Investigating ways to improve immune tolerance in Pompe
Immune tolerance induction is a strategy to limit this antibody response. One approach uses transient low-dose methotrexate, or TLD-MTX, which is a short course of an immune-system suppressant medication. But how MTX-induced immune tolerance works remains unclear.
To investigate, researchers at Duke, in North Carolina, analyzed blood samples from IOPD and LOPD patients who underwent six months of the ERT Lumizyme (alglucosidade alfa) plus TLD-MTX.
The LOPD group, who ranged in age from 31 to 77, comprised six patients with paired samples taken before and after treatment. The IOPD group, which involved children ages 1-11 months, used 13 unpaired samples — three from treated patients and 10 from those who didn’t receive treatment and served as an IOPD control group.
The TLD-MTX regimen consisted of three cycles of three daily methotrexate doses, given orally or as under-the-skin (subcutaneous) injections, starting with the first Lumizyme dose. The team counted and classified immune cells from blood samples and measured disease activity with urinary glucose tetrasaccharide (Glc4), a glycogen breakdown product.
Better results seen for patients given methotrexate
The data showed that treated IOPD patients had fewer immune monocyte cells that carry the CD16 marker, which are generally considered more proinflammatory. At the same time, classical CD14-positive/CD16-negative monocytes were more frequent. This group also had more CD14-positive monocytes and fewer dendritic cells, which help activate other immune cells.
Plasmablasts, early antibody-producing B-cells, were nearly fivefold lower with treatment. This suggests that MTX may suppress the growth of these cells and/or dampen inflammation associated with glycogen accumulation, the team noted.
Meanwhile, mature memory B-cells, which maintain long-term immunity, more than doubled, suggesting a “shift from an inflammatory immune response to a more regulated, memory-focused immune state,” the researchers wrote. The team also found fewer memory T-cells, which help drive immune responses.
Samples from LOPD patients showed a decrease in B-cells after treatment, while plasmablasts and the proportion of memory B-cells relative to other types of B-cells increased. T-cells with the CD4 marker and the TIGIT receptor also increased, which “may reflect a regulatory mechanism contributing to immune tolerance,” the team wrote.
Pretreatment urinary Glc4 levels were higher in IOPD than LOPD patients and decreased in both groups after ERT plus MTX, “reflecting clearance of glycogen and decreased disease activity,” the researchers wrote.
The addition of [methotrexate] may further modulate chronic inflammation and shift immune cell profiles toward a more regulated state in both IOPD and LOPD patients, potentially improving clinical outcomes.
One of the three treated IOPD patients developed high antibody levels, which peaked at six months and declined by month nine. Among the LOPD patients, TLD-MTX induced lasting immune tolerance, defined as the absence of anti-GAA antibodies, in four of the six patients. All other patients receiving MTX maintained low antibody levels throughout the follow-up period.
According to researchers, the results demonstrate distinct immune profiles before and after ERT with methotrexate in IOPD and LOPD patients. The team added that methotrexate may further modulate immune responses to reduce anti-ERT antibodies.
The scientists concluded that “the addition of [methotrexate] may further modulate chronic inflammation and shift immune cell profiles toward a more regulated state in both IOPD and LOPD patients, potentially improving clinical outcomes.”
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