Novel approach to idursulfase and laronidase desensitization in type 2 and type 1 S mucopolysaccharidosis (MPS).

Idursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization. Two patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication. Rapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance.

Spataro F ，Viggiani F ，Macchia DG ，Rollo V ，Tummolo A ，Suppressa P ，Sabba' C ，Rossi MP ，Giliberti L ，Satriano F ，Nettis E ，Di Bona D ，Caiaffa MF ，Fischetto R ，Macchia L ... -  《Orphanet Journal of Rare Diseases》

Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome).

da Silva EM ，Strufaldi MW ，Andriolo RB ，Silva LA ... -  《-》

Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome).

da Silva EM ，Strufaldi MW ，Andriolo RB ，Silva LA ... -  《-》

IgE-mediated anaphylaxis and allergic reactions to idursulfase in patients with Hunter syndrome.

Enzyme replacement therapy (ERT) with recombinant human idursulfase is effective for the treatment of Hunter syndrome, mucopolysaccharidosis (MPS) type II. However, various adverse events can occur by the infusion of idursulfase. The purpose was to evaluate the occurrence of infusion-related allergic reactions, including anaphylaxis, to idursulfase in patients with MPS II receiving ERT and to elucidate its possible mechanism. A total of 34 patients with MPS II were enrolled to receive ERT with Elaprase(®) at a dose of 0.5 mg/kg intravenously once a week. Information regarding the symptoms, frequency, and timing of anaphylaxis during treatment was analyzed. Presence of anti-idursulfase IgE antibody was assessed by skin prick test (SPT) and enzyme-linked immunosorbent assay (ELISA). Western blotting was performed to confirm the reaction between idursulfase and specific IgE. Three patients (8.8%) showed anaphylaxis by infusion of idursulfase. No deaths occurred during the study. Anti-idursulfase IgE antibody was detected by SPT and ELISA. Immunoblotting with patients' sera and Elaprase(®) showed a single band of specific IgE binding to the protein around 70 kD, and idursulfase did not display amino acid sequence homology to known allergens. SPT with idursulfase demonstrated positive results in all patients with anaphylaxis. However, we failed to reveal any risk factors for the development of infusion-related immediate-type allergic reactions. Anaphylaxis related to infusion of idursulfase is mediated by anti-idursulfase IgE antibody, which might be produced by de novo synthesis. SPT is useful in predicting the occurrence of anti-idursulfase IgE-mediated anaphylaxis during infusion.

Kim J ，Park MR ，Kim DS ，Lee JO ，Maeng SH ，Cho SY ，Han Y ，Ahn K ，Jin DK ... -  《-》

Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome).

da Silva EM ，Strufaldi MW ，Andriolo RB ，Silva LA ... -  《-》