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Monitoring the 3-year efficacy of enzyme replacement therapy in fabry disease by repeated skin biopsies.

The earliest clinical signs of Fabry disease often manifest as dermatologic disturbances such as angiokeratomata, hypohidrosis, acroparesthesias, and impaired thermal and vibration detection. These disturbances are caused by cellular globotriaosylceramide accumulation in the skin due to deficient lysosomal alpha-galactosidase A activity. In this histologic study, we analyzed pre- and post-treatment dermatologic biopsies from 58 Fabry patients enrolled in a 5 mo, Phase 3 double-blind, randomized, placebo-controlled trial followed by a 30 mo open label extension study of recombinant human alpha-galactosidase A (r-halphaGalA), administered i.v. at 1 mg per kg every 2 wk. Baseline evaluations revealed globotriaosylceramide in multiple dermal cell types (vascular endothelial cells, vascular smooth muscle cells, perineurium). Five months of r-halphaGalA treatment in the Phase 3 trial resulted in complete clearance of globotriaosylceramide from the superficial capillary endothelium in all treatment patients and in only 1 (3%) placebo patient (p<0.001). The placebo group achieved similar results after 6 mo of r-halphaGalA in the open label trial. The capillary endothelium remained free of globotriaosylceramide for up to 30 mo into the extension study among 39 of 40 (98%) patients who underwent biopsies. Globotriaosylceramide clearance from deep vascular endothelial cells was similarly robust. Vascular smooth muscle cells and perineurium demonstrated moderate clearance. These findings suggest that long-term treatment with r-halphaGalA may halt the progression of pathology and prevent the dermatologic disturbances in Fabry patients, and that periodic dermal biopsies can serve as a reliable monitor of sustained efficacy.