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• W3210368816 abstract "Clinical ImplicationsEnzyme replacement therapy (ERT) discontinuation significantly worsens visceromegaly, respiratory function, and walking capacity in patients with mucopolysaccharidoses. Because ERT is the only possible therapeutic alternative for most patients, hypersensitivity reactions are a cause of early treatment discontinuation. Patients experiencing hypersensitivity reactions to ERT can benefit from rapid desensitization to receive their treatment safely.Patients with mucopolysaccharidoses (MPS) display deficient lysosomal enzymes leading to the accumulation of glycosaminoglycan in a myriad of cells and tissues. Multiple organs malfunction and abnormalities in growth and development have been described in these patients.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google ScholarEnzyme replacement therapy (ERT) is the most important therapeutic strategy for MPS patients, slowing the disease progression, ameliorating the symptoms, and improving health-related quality of life.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google Scholar Specific enzymatic treatment is available for patients with MPS I, II, IVA, VI, and VII.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google Scholar Except for vestronidase alfa-vjbk (which is administered biweekly), the recombinant enzymes are administered in weekly intravenous infusions.Enzyme infusion–related immediate hypersensitivity reactions (IHRs) are infrequent, and they can be mild to moderate, including cutaneous, gastrointestinal, and respiratory symptoms.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google ScholarRapid drug desensitization (RDD) is a therapeutic technique that modifies the immune response of allergic patients to those drugs they are allergic to. The RDD induces a temporary tolerance that can only be maintained while drug serum levels are maintained, and the temporary tolerance is lost as soon as the drug is eliminated.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Based on in vivo and in vitro evidence, RDD protocols follow specific methodology, namely, starting at very low doses that are subthreshold for anaphylaxis, with doses doubling every 15 to 30 minutes at each increment until the target dose is attained. In previous experience with platins, RDD has shown to be cost-effective and to not affect the efficacy of the drug.3Sloane D. Govindarajulu U. Harrow-Mortelliti J. Barry W. Hsu F.I. Hong D. et al.Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.J Allergy Clin Immunol Pract. 2016; 4: 497-504Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar RDD is the only hope to continue life-saving treatment in patients who react to first-line therapies and have no equally efficacious treatment alternatives. Enzyme replacement therapy (ERT) is vital in patients with MPS. We evaluated the efficacy and the safety of RDD in Latin American patients with MPS IVA and VI who experienced infusion-induced IHR.We conducted a multicentric retrospective observational study between July 2012 and September 2020 including patients from Brazil (São Paulo, Belo Horizonte, Florianópolis, and Porto Alegre) and Colombia (Bogota) diagnosed with MPS IVA or VI receiving elosulfase alfa or galsulfase who presented with IHR regardless of severity. There were no exclusion criteria or sample size calculations because of the rarity of the condition. The study was approved by the Institutional Ethic Committee and informed consent was obtained from all patients (or their parents, when legally obliged) prior to inclusion in the study.A survey containing questions about demographic data, biochemical and genetic diagnosis, ERT initiation, and the information regarding the IHR and the RDD protocol was sent to the physicians who retrieved data from the medical records of the participants.Immediate readings for skin prick and intradermal tests were used as in vivo biomarkers for immunoglobulin E (IgE)–mediated sensitization.4Brockow K. Garvey L.H. Aberer W. Atanaskovic-Markovic M. Barbaud A. Bilo M.B. et al.Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2013; 68: 702-712Crossref PubMed Scopus (605) Google Scholar The skin prick tests were performed using an undiluted aliquot of the enzyme. The intradermal tests were performed with diluted (1/100 and 1/10) and pure concentrations according to our previous data showing this is nonirritating.5Aranda C.S. Ensina L.F. Nunes I.C. Mallozi M.C. Mendes C. Martins A.M. et al.Diagnosis and management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases: the role of desensitization.J Allergy Clin Immunol Pract. 2016; 4: 354-356Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Both tests were performed and interpreted according to the European guidelines.4Brockow K. Garvey L.H. Aberer W. Atanaskovic-Markovic M. Barbaud A. Bilo M.B. et al.Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2013; 68: 702-712Crossref PubMed Scopus (605) Google ScholarAs per standard guidance,2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar we decided to offer RDD for patients with a confirmed hypersensitivity reaction with no equally effective therapeutic alternative. Because all patients had positive skin tests and were in need of ERT, all patients were offered RDD. Therefore, the RDD consisted of administrating elosulfase alfa (MPS IVA) or galsulfase (MPS VI) in a 12-step or a 16-step protocol as proposed by Castells and coauthors.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar,6Castells M.C. Tennant N.M. Sloane D.E. Hsu F.I. Barrett N.A. Hong D.I. et al.Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.J Allergy Clin Immunol. 2008; 122: 574-580Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar The choice between both protocols was performed based on risk stratification, according to the severity of the initial reaction, as previously described by Sloane and colleagues.3Sloane D. Govindarajulu U. Harrow-Mortelliti J. Barry W. Hsu F.I. Hong D. et al.Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.J Allergy Clin Immunol Pract. 2016; 4: 497-504Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar All protocols were performed in settings in which resuscitation personnel and resources were readily available.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google ScholarAll the enzyme infusions were only conducted if patients were considered healthy. In addition, the patient could not have any infections or being under antibiotics for 72 hour prior to the infusion.Of the 6 enrolled patients, 3 (50%) were diagnosed with MPS IVA and 3 (50%) had MPS VI. Only 1 patient was male (with MPS VI). The median age of the patients was 11.3 years (SD 10.8 years) and they started receiving ERT at the median age of 5.2 years (SD 11.14 years). The ERT-induced IHR onset occurred after 1.1 years of treatment (SD 1.7 years). Demographic data are detailed in Table E1 (available in this article’s Online Repository at www.jaci-inpractice.org).The severity of the reactions was classified using the grading system of the World Allergy Organization.7Cardona V. Ansotegui I.J. Ebisawa M. El-Gamal Y. Fernandez Rivas M. Fineman S. et al.World allergy organization anaphylaxis guidance 2020.World Allergy Organ J. 2020; 13: 100472Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar The initial anaphylactic reactions included skin manifestations (83%; 5 of 6), gastrointestinal symptoms (67%; 4 of 6), and tachycardia (33%; 2 of 6). One MPS IVA patient displayed reduced pulse oximetry associated with vomiting during infusion, and the IHR was deemed as grade 3 (accordingly to the World Allergy Organization consensus document7Cardona V. Ansotegui I.J. Ebisawa M. El-Gamal Y. Fernandez Rivas M. Fineman S. et al.World allergy organization anaphylaxis guidance 2020.World Allergy Organ J. 2020; 13: 100472Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar) (Table I).Table ICharacterization of the IRR and the breakthrough reactions presented by the enrolled patients before and after the RDDPatient numberERT-induced IHRBrown classification of IHRSPTIDTBreakthrough reactions during the RDDBreakthrough reactions clinical featuresBreakthrough reactions∗The severity of the reactions was classified using the grading system of the World Allergy Organization.Management of future RDDs1Flushing (erythema and/or warmth), pruritus, urticarial, and nauseaGrade 2PositivePositiveYesStep 12 (twice)Flushing (erythema and/or warmth), pruritusGrade 1Change from 12-step to 16-step protocol2Vomiting and SpO2 < 92% at any stageGrade 3NAPositiveNoNoNAChange from 16-step to 12-step protocol3Flushing (erythema and/or warmth), pruritus, urticarial, and tachycardiaGrade 1PositivePositiveNoNoNANA4Flushing (erythema and/or warmth), pruritus, urticaria, tachycardia, and vomitingGrade 2PositiveNAYesStep 12UrticariaGrade 1Change from 12-step to 16-step protocol5Flushing (erythema and/or warmth), pruritus, urticarial, and vomitingGrade 2PositivePositiveYesVarious steps†Patient 5 presented with 12 breakthrough reactions. Three of those reactions occurred during the 10th and 12th steps of the 12-step RDD protocol and the remaining ones were observed during the last step of the 16-step protocol.Pruritus, urticarial, and nauseaGrade 2Change from 12-step to 16-step protocol and administration of omalizumab6Flushing (erythema and/or warmth), pruritus, and urticariaGrade 1PositivePositiveNoNoNANAIDT, Intradermal test; NA, not available/not assessed; SpO2, pulse oximetry; SPT, skin prick test.∗ The severity of the reactions was classified using the grading system of the World Allergy Organization.† Patient 5 presented with 12 breakthrough reactions. Three of those reactions occurred during the 10th and 12th steps of the 12-step RDD protocol and the remaining ones were observed during the last step of the 16-step protocol. Open table in a new tab All patients underwent the 12-step or the 16-step RDD protocols (Table I) and 1,008 RDDs were conducted (Figure 1). All patients received antihistamines before the infusion even though it is not preconized that ERT should be preceded by premedication (Table E2; available in this article’s Online Repository at www.jaci-inpractice.org). Owing to breakthrough reactions, 3 patients (1, 4, and 5) also received steroids. The rate of breakthrough reactions was 1.5% (15 of 1,008 in 3 patients). Two patients (1 and 4) displayed cutaneous symptoms and nausea that were successfully treated, and the subsequent infusion was performed under the 16-step protocol. Patient 5 had a total of 12 breakthrough reactions. After the first reaction, the patient was switched to a 16-step RDD protocol and higher doses of premedication were also administered but unsuccessfully prevented another IHR. Omalizumab, an anti-IgE drug (a monthly dose of 150 mg), was thus added on as previously described8Mishra S. Connors L. Tugwell B. Role of omalizumab in insulin hypersensitivity: a case report and review of the literature.Diabet Med. 2018; 35: 663-666Crossref PubMed Scopus (12) Google Scholar and the patient stopped reacting during ERT (Table I).Our data demonstrated that RDD is safe and efficacious in maintaining ERT for individuals with MPS IVA and VI and enzyme-induced IHR. Fifty percent of the patients experienced at least 1 breakthrough reaction during RDD. However, all patients achieved uneventful tolerance after adjustments to their RDD protocols, as per standard recommendations.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google ScholarEnsina and coworkers9Ensina L.F. Aranda C.S. de Lacerda A.E. Camelo-Nunes I. Sole D. Martins A.M. et al.Laronidase hypersensitivity and desensitization in type I mucopolysaccharidosis: a case report.Pediatr Allergy Immunol. 2014; 25: 498-499Crossref PubMed Scopus (16) Google Scholar demonstrated that the RDD was effective in controlling a laronidase-induced IHR in an MPS I patient, indicating that such a protocol could be extended to patients with lysosomal storage disorders. This conjecture was confirmed by Aranda et al,5Aranda C.S. Ensina L.F. Nunes I.C. Mallozi M.C. Mendes C. Martins A.M. et al.Diagnosis and management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases: the role of desensitization.J Allergy Clin Immunol Pract. 2016; 4: 354-356Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar who employed this protocol to manage IHR to ERT in patients with Pompe, Gaucher, and Fabry syndromes and MPS.The positive skin tests results suggest an involvement of specific IgE-activating mast cells or basophils. These results corroborate the hypothesis that ERT can induce a specific immune response. Notably, omalizumab administration led to a complete control of breakthrough reactions, thus indicating a pathogenic role of IgE in the development of those allergic reactions.RDD, using validated protocols by Castells et al,6Castells M.C. Tennant N.M. Sloane D.E. Hsu F.I. Barrett N.A. Hong D.I. et al.Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.J Allergy Clin Immunol. 2008; 122: 574-580Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar was safe and efficacious in maintaining ERT for individuals with MPS IVA and VI and enzyme-induced IHR.5Aranda C.S. Ensina L.F. Nunes I.C. Mallozi M.C. Mendes C. Martins A.M. et al.Diagnosis and management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases: the role of desensitization.J Allergy Clin Immunol Pract. 2016; 4: 354-356Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,6Castells M.C. Tennant N.M. Sloane D.E. Hsu F.I. Barrett N.A. Hong D.I. et al.Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.J Allergy Clin Immunol. 2008; 122: 574-580Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar These findings demonstrate an important strategy for maintaining specific therapies in these patients, thus contributing to delayed disease progression and avoiding the reduction of their health-related quality of life.AcknowledgmentsThe authors would like to thank Tatiana Magalhaes, MD, and Debora Mesojedovas, PharmD, of BioMarin Latin America for contributions and BioMarin Brasil Farmacêutica Ltda., which sponsored the preparation of this article and reviewed the article for medical and scientific accuracy. A special thanks to Camilla Patti Hissamura, PhD who was the medical writer of this manuscript.Author contributionsC. S. Aranda, M. V. Aun, A. M. Martins, and D. Solé conceived the manuscript. C. S. Aranda, C. F. M. de Souza, L. L. d. C. Pinto, G. L. Porras-Hurtado, O. F. S. Salgado, and R. R. Arantes collected the data. All authors critically revised the text and approved the final manuscript. Clinical ImplicationsEnzyme replacement therapy (ERT) discontinuation significantly worsens visceromegaly, respiratory function, and walking capacity in patients with mucopolysaccharidoses. Because ERT is the only possible therapeutic alternative for most patients, hypersensitivity reactions are a cause of early treatment discontinuation. Patients experiencing hypersensitivity reactions to ERT can benefit from rapid desensitization to receive their treatment safely. Enzyme replacement therapy (ERT) discontinuation significantly worsens visceromegaly, respiratory function, and walking capacity in patients with mucopolysaccharidoses. Because ERT is the only possible therapeutic alternative for most patients, hypersensitivity reactions are a cause of early treatment discontinuation. Patients experiencing hypersensitivity reactions to ERT can benefit from rapid desensitization to receive their treatment safely. Enzyme replacement therapy (ERT) discontinuation significantly worsens visceromegaly, respiratory function, and walking capacity in patients with mucopolysaccharidoses. Because ERT is the only possible therapeutic alternative for most patients, hypersensitivity reactions are a cause of early treatment discontinuation. Patients experiencing hypersensitivity reactions to ERT can benefit from rapid desensitization to receive their treatment safely. Patients with mucopolysaccharidoses (MPS) display deficient lysosomal enzymes leading to the accumulation of glycosaminoglycan in a myriad of cells and tissues. Multiple organs malfunction and abnormalities in growth and development have been described in these patients.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google Scholar Enzyme replacement therapy (ERT) is the most important therapeutic strategy for MPS patients, slowing the disease progression, ameliorating the symptoms, and improving health-related quality of life.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google Scholar Specific enzymatic treatment is available for patients with MPS I, II, IVA, VI, and VII.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google Scholar Except for vestronidase alfa-vjbk (which is administered biweekly), the recombinant enzymes are administered in weekly intravenous infusions. Enzyme infusion–related immediate hypersensitivity reactions (IHRs) are infrequent, and they can be mild to moderate, including cutaneous, gastrointestinal, and respiratory symptoms.1Concolino D. Deodato F. Parini R. Enzyme replacement therapy: efficacy and limitations.Ital J Pediatr. 2018; 44: 120Crossref PubMed Scopus (81) Google Scholar Rapid drug desensitization (RDD) is a therapeutic technique that modifies the immune response of allergic patients to those drugs they are allergic to. The RDD induces a temporary tolerance that can only be maintained while drug serum levels are maintained, and the temporary tolerance is lost as soon as the drug is eliminated.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Based on in vivo and in vitro evidence, RDD protocols follow specific methodology, namely, starting at very low doses that are subthreshold for anaphylaxis, with doses doubling every 15 to 30 minutes at each increment until the target dose is attained. In previous experience with platins, RDD has shown to be cost-effective and to not affect the efficacy of the drug.3Sloane D. Govindarajulu U. Harrow-Mortelliti J. Barry W. Hsu F.I. Hong D. et al.Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.J Allergy Clin Immunol Pract. 2016; 4: 497-504Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar RDD is the only hope to continue life-saving treatment in patients who react to first-line therapies and have no equally efficacious treatment alternatives. Enzyme replacement therapy (ERT) is vital in patients with MPS. We evaluated the efficacy and the safety of RDD in Latin American patients with MPS IVA and VI who experienced infusion-induced IHR. We conducted a multicentric retrospective observational study between July 2012 and September 2020 including patients from Brazil (São Paulo, Belo Horizonte, Florianópolis, and Porto Alegre) and Colombia (Bogota) diagnosed with MPS IVA or VI receiving elosulfase alfa or galsulfase who presented with IHR regardless of severity. There were no exclusion criteria or sample size calculations because of the rarity of the condition. The study was approved by the Institutional Ethic Committee and informed consent was obtained from all patients (or their parents, when legally obliged) prior to inclusion in the study. A survey containing questions about demographic data, biochemical and genetic diagnosis, ERT initiation, and the information regarding the IHR and the RDD protocol was sent to the physicians who retrieved data from the medical records of the participants. Immediate readings for skin prick and intradermal tests were used as in vivo biomarkers for immunoglobulin E (IgE)–mediated sensitization.4Brockow K. Garvey L.H. Aberer W. Atanaskovic-Markovic M. Barbaud A. Bilo M.B. et al.Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2013; 68: 702-712Crossref PubMed Scopus (605) Google Scholar The skin prick tests were performed using an undiluted aliquot of the enzyme. The intradermal tests were performed with diluted (1/100 and 1/10) and pure concentrations according to our previous data showing this is nonirritating.5Aranda C.S. Ensina L.F. Nunes I.C. Mallozi M.C. Mendes C. Martins A.M. et al.Diagnosis and management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases: the role of desensitization.J Allergy Clin Immunol Pract. 2016; 4: 354-356Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Both tests were performed and interpreted according to the European guidelines.4Brockow K. Garvey L.H. Aberer W. Atanaskovic-Markovic M. Barbaud A. Bilo M.B. et al.Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2013; 68: 702-712Crossref PubMed Scopus (605) Google Scholar As per standard guidance,2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar we decided to offer RDD for patients with a confirmed hypersensitivity reaction with no equally effective therapeutic alternative. Because all patients had positive skin tests and were in need of ERT, all patients were offered RDD. Therefore, the RDD consisted of administrating elosulfase alfa (MPS IVA) or galsulfase (MPS VI) in a 12-step or a 16-step protocol as proposed by Castells and coauthors.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar,6Castells M.C. Tennant N.M. Sloane D.E. Hsu F.I. Barrett N.A. Hong D.I. et al.Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.J Allergy Clin Immunol. 2008; 122: 574-580Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar The choice between both protocols was performed based on risk stratification, according to the severity of the initial reaction, as previously described by Sloane and colleagues.3Sloane D. Govindarajulu U. Harrow-Mortelliti J. Barry W. Hsu F.I. Hong D. et al.Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.J Allergy Clin Immunol Pract. 2016; 4: 497-504Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar All protocols were performed in settings in which resuscitation personnel and resources were readily available.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar All the enzyme infusions were only conducted if patients were considered healthy. In addition, the patient could not have any infections or being under antibiotics for 72 hour prior to the infusion. Of the 6 enrolled patients, 3 (50%) were diagnosed with MPS IVA and 3 (50%) had MPS VI. Only 1 patient was male (with MPS VI). The median age of the patients was 11.3 years (SD 10.8 years) and they started receiving ERT at the median age of 5.2 years (SD 11.14 years). The ERT-induced IHR onset occurred after 1.1 years of treatment (SD 1.7 years). Demographic data are detailed in Table E1 (available in this article’s Online Repository at www.jaci-inpractice.org). The severity of the reactions was classified using the grading system of the World Allergy Organization.7Cardona V. Ansotegui I.J. Ebisawa M. El-Gamal Y. Fernandez Rivas M. Fineman S. et al.World allergy organization anaphylaxis guidance 2020.World Allergy Organ J. 2020; 13: 100472Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar The initial anaphylactic reactions included skin manifestations (83%; 5 of 6), gastrointestinal symptoms (67%; 4 of 6), and tachycardia (33%; 2 of 6). One MPS IVA patient displayed reduced pulse oximetry associated with vomiting during infusion, and the IHR was deemed as grade 3 (accordingly to the World Allergy Organization consensus document7Cardona V. Ansotegui I.J. Ebisawa M. El-Gamal Y. Fernandez Rivas M. Fineman S. et al.World allergy organization anaphylaxis guidance 2020.World Allergy Organ J. 2020; 13: 100472Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar) (Table I). IDT, Intradermal test; NA, not available/not assessed; SpO2, pulse oximetry; SPT, skin prick test. All patients underwent the 12-step or the 16-step RDD protocols (Table I) and 1,008 RDDs were conducted (Figure 1). All patients received antihistamines before the infusion even though it is not preconized that ERT should be preceded by premedication (Table E2; available in this article’s Online Repository at www.jaci-inpractice.org). Owing to breakthrough reactions, 3 patients (1, 4, and 5) also received steroids. The rate of breakthrough reactions was 1.5% (15 of 1,008 in 3 patients). Two patients (1 and 4) displayed cutaneous symptoms and nausea that were successfully treated, and the subsequent infusion was performed under the 16-step protocol. Patient 5 had a total of 12 breakthrough reactions. After the first reaction, the patient was switched to a 16-step RDD protocol and higher doses of premedication were also administered but unsuccessfully prevented another IHR. Omalizumab, an anti-IgE drug (a monthly dose of 150 mg), was thus added on as previously described8Mishra S. Connors L. Tugwell B. Role of omalizumab in insulin hypersensitivity: a case report and review of the literature.Diabet Med. 2018; 35: 663-666Crossref PubMed Scopus (12) Google Scholar and the patient stopped reacting during ERT (Table I). Our data demonstrated that RDD is safe and efficacious in maintaining ERT for individuals with MPS IVA and VI and enzyme-induced IHR. Fifty percent of the patients experienced at least 1 breakthrough reaction during RDD. However, all patients achieved uneventful tolerance after adjustments to their RDD protocols, as per standard recommendations.2Broyles A.D. Banerji A. Castells M. Practical guidance for the evaluation and management of drug hypersensitivity: general concepts.J Allergy Clin Immunol Pract. 2020; 8: S3-S15Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Ensina and coworkers9Ensina L.F. Aranda C.S. de Lacerda A.E. Camelo-Nunes I. Sole D. Martins A.M. et al.Laronidase hypersensitivity and desensitization in type I mucopolysaccharidosis: a case report.Pediatr Allergy Immunol. 2014; 25: 498-499Crossref PubMed Scopus (16) Google Scholar demonstrated that the RDD was effective in controlling a laronidase-induced IHR in an MPS I patient, indicating that such a protocol could be extended to patients with lysosomal storage disorders. This conjecture was confirmed by Aranda et al,5Aranda C.S. Ensina L.F. Nunes I.C. Mallozi M.C. Mendes C. Martins A.M. et al.Diagnosis and management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases: the role of desensitization.J Allergy Clin Immunol Pract. 2016; 4: 354-356Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar who employed this protocol to manage IHR to ERT in patients with Pompe, Gaucher, and Fabry syndromes and MPS. The positive skin tests results suggest an involvement of specific IgE-activating mast cells or basophils. These results corroborate the hypothesis that ERT can induce a specific immune response. Notably, omalizumab administration led to a complete control of breakthrough reactions, thus indicating a pathogenic role of IgE in the development of those allergic reactions. RDD, using validated protocols by Castells et al,6Castells M.C. Tennant N.M. Sloane D.E. Hsu F.I. Barrett N.A. Hong D.I. et al.Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.J Allergy Clin Immunol. 2008; 122: 574-580Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar was safe and efficacious in maintaining ERT for individuals with MPS IVA and VI and enzyme-induced IHR.5Aranda C.S. Ensina L.F. Nunes I.C. Mallozi M.C. Mendes C. Martins A.M. et al.Diagnosis and management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases: the role of desensitization.J Allergy Clin Immunol Pract. 2016; 4: 354-356Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,6Castells M.C. Tennant N.M. Sloane D.E. Hsu F.I. Barrett N.A. Hong D.I. et al.Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.J Allergy Clin Immunol. 2008; 122: 574-580Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar These findings demonstrate an important strategy for maintaining specific therapies in these patients, thus contributing to delayed disease progression and avoiding the reduction of their health-related quality of life. AcknowledgmentsThe authors would like to thank Tatiana Magalhaes, MD, and Debora Mesojedovas, PharmD, of BioMarin Latin America for contributions and BioMarin Brasil Farmacêutica Ltda., which sponsored the preparation of this article and reviewed the article for medical and scientific accuracy. A special thanks to Camilla Patti Hissamura, PhD who was the medical writer of this manuscript.Author contributionsC. S. Aranda, M. V. Aun, A. M. Martins, and D. Solé conceived the manuscript. C. S. Aranda, C. F. M. de Souza, L. L. d. C. Pinto, G. L. Porras-Hurtado, O. F. S. Salgado, and R. R. Arantes collected the data. All authors critically revised the text and approved the final manuscript. The authors would like to thank Tatiana Magalhaes, MD, and Debora Mesojedovas, PharmD, of BioMarin Latin America for contributions and BioMarin Brasil Farmacêutica Ltda., which sponsored the preparation of this article and reviewed the article for medical and scientific accuracy. A special thanks to Camilla Patti Hissamura, PhD who was the medical writer of this manuscript. Author contributionsC. S. Aranda, M. V. Aun, A. M. Martins, and D. Solé conceived the manuscript. C. S. Aranda, C. F. M. de Souza, L. L. d. C. Pinto, G. L. Porras-Hurtado, O. F. S. Salgado, and R. R. Arantes collected the data. All authors critically revised the text and approved the final manuscript. C. S. Aranda, M. V. Aun, A. M. Martins, and D. Solé conceived the manuscript. C. S. Aranda, C. F. M. de Souza, L. L. d. C. Pinto, G. L. Porras-Hurtado, O. F. S. Salgado, and R. R. Arantes collected the data. All authors critically revised the text and approved the final manuscript. Online RepositoryTable E1Demographic data of the patients enrolled in the study∗All patients had mutations in homozygosis.Patient numberMPS typeMutationsAge (y)Age at diagnosis (y)SexAge at ERT initiation (y)Interval between the age at diagnosis and ERT initiation (y)Any ERT interruption?Interval between the ERT initiation and the IHR onset (y)1IVAp.Gly116Ser17.87.2Female10.83.6No3.62IVAp.Gly11Ser10.24.7Female8.13.4No0.23IVAp.Gly301Cys37.13.3Female33.22.9No0.14VIp.Arg315Gln5.11.4Female1.60.1No0.55VIp.Leu72Arg12.31.3Male1.50.2No4.36VIp.Arg315Gln6.31.7Female2.30.6Yes1.8∗ All patients had mutations in homozygosis. Open table in a new tab Table E2Personalized premedication administrated to the patients enrolled in the study based on the medical needDrugDose and route of administrationDiphenhydramine200 mg, IVDesloratadine5 mg, POCetirizine5 mg, POOndansetron4 mg, PORanitidine20 mg, IVHydrocortisone100 mg, IVPredinisone30 mg, POMethylpredinisone16 mg, POMontelukast4 mg, POAcetylsalicylic acid100 mg, POAcetominophen7 drops, POOmalizumab75 mg, SCIV, Intravenous; PO, by mouth; SC, subcutaneous. Open table in a new tab IV, Intravenous; PO, by mouth; SC, subcutaneous." @default.
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