ERT treatment guidelines lead to stable Fabry in women: Study
Treatment decisions tied to disease severity appear correct, per analysis
Women severely affected by Fabry disease and treated with enzyme replacement therapy (ERT) and untreated women with less severe symptoms showed broadly stable disease course over five years, a study in Germany found.
Treatment decisions were primarily based on the European guidelines for females with Fabry, which recommend initiating treatment at the first manifestation of Fabry-related organ involvement or pain. The guidelines “appear to have been correct” for most of the women in the study, the researchers wrote. Still, “it is crucial to explore if organ involvement is [Fabry]-related in order to make the correct treatment decision,” they wrote.
The study, “Impact of enzyme replacement therapy on clinical manifestations in females with Fabry disease,“ which was published in the Orphanet Journal of Rare Diseases.
According to current European guidelines, ERT for female Fabry patients should start after the first manifestation involving the kidneys, heart, or nervous system, or if pain or severe gastrointestinal complaints are present.
A previous study from the research team suggested that treatment for women with Fabry in that country generally aligns with the current European Fabry guidelines. Still, one-third of patients were left untreated despite organ involvement.
More variable symptoms in women
In Fabry, mutations in the GLA gene disrupt the production and/or function of the enzyme alpha-galactosidase A (alpha-Gal A). A lack of this enzyme’s activity leads to the toxic build-up of fatty substances called globotriaosylceramide (Gb3) and lyso-Gb3 in the body’s cells, particularly in the heart, kidneys, and nervous system.
Because the GLA gene is located on the X chromosome, males with one copy of the gene tend to have more severe symptoms that develop earlier than females with two copies. For females, even if one copy of the GLA gene is mutated, the second copy is typically normal, so disease onset, progression, and severity varies more than in males.
The researchers said this discrepancy means more data are required for female patients to analyze the effect of ERT or to exclude potential disease progression in untreated females. They retrospectively analyzed data from 159 women with Fabry collected at three visits at six Fabry centers in Germany. All participants were either untreated with ERT or on a stable dose of agalsidase alfa, sold as Replagal outside the U.S., or agalsidase-beta, sold as Fabrazyme, for at least six months.
Seventy-one patients were untreated, 47 were newly treated, and 41 had received long-term ERT. The untreated group was significantly younger, had the lowest blood levels of lyso-Gb3, and had the least frequent Fabry-related symptoms and manifestations, including edema (swelling), pain, fatigue, and heart involvement.
The newly ERT-treated group had the highest blood pressure values and showed more frequent albuminuria, a sign of kidney disease. Median eGFR values, a test for kidney function, and the number of ischemic attacks/strokes were similar before the first visit across all three groups.
Fabry-related pain was the most frequent initial manifestation in all three groups, followed by heart and kidney involvement. Gastrointestinal symptoms were reported by 37.3% of untreated patients.
ERT and organs
About 90% of patients who received ERT showed at least one organ manifestation, with most having two or more, “justifying treatment according to current European guidelines,” the team noted. In contrast, one in four untreated patients showed no organ damage or manifestations at the first visit, and one-third had more than one manifestation.
Between the first and third visits, transient ischemic attacks/strokes occurred more often among newly ERT-treated patients than in untreated and long-term ERT patients. Four of the five newly treated patients who experienced these events had no history of such complications.
At the same time, heart involvement remained stable across all three groups. No pacemakers for irregular heartbeats were needed among untreated patients, while nearly 1 in 10 (8.5%) newly treated patients and 1 in 20 (4.5%) long-term ERT patients required pacemakers.
Mean eGFRs for kidney function in newly treated and long-term ERT-treated patients slightly decreased over time, but remained stable within the untreated group. The albumin-to-creatinine ratio from urine, another kidney function test, was stable in all three groups over time.
Disease severity slightly increased over time in all groups, as indicated by the Disease Severity Scoring System (DS3) and the Mainz Severity Score Index (MSSI). Blood tests showed lyso-Gb3 values in the newly ERT-treated group dropped significantly over time while remaining stable in the other two groups.
“Both severely affected females who were treated and less severely affected untreated females showed a broadly stable disease course over 5 years,” the researchers wrote. “The treatment decisions based on the European guidelines appear to have been correct in most patients of our cohort.”
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