205 results on '"Hershfield, Ms"'
Search Results
2. Diagnosis of deficiency of adenosine deaminase type 2 in adulthood
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Betrains, A, primary, Staels, F, additional, Moens, L, additional, Delafontaine, S, additional, Hershfield, MS, additional, Blockmans, D, additional, Liston, A, additional, Humblet-Baron, S, additional, Meyts, I, additional, Schrijvers, R, additional, and Vanderschueren, S, additional
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- 2021
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3. Generation of normal lymphocyte populations following transplantation of adenosine–deaminase-deficient fetal liver cells
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Migchielsen, AAJ, Knaän-Schanzer, S, Breuer, ML, Hershfield, MS, and Valerio, D
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- 1997
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4. Delayed-onset adenosine deaminase deficiency: Strategies for an early diagnosis
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Speckmann, C., Neumann, C., Borte, S., giancarlo la marca, Sass, Jo, Wiech, E., Fisch, P., Schwarz, K., Buchholz, B., Schlesier, M., Felgentreff, K., Grimbacher, B., Santisteban, I., Bali, P., Hershfield, Ms, and Ehl, S.
- Published
- 2012
5. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update
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Saito, Y, primary, Stamp, LK, additional, Caudle, KE, additional, Hershfield, MS, additional, McDonagh, EM, additional, Callaghan, JT, additional, Tassaneeyakul, W, additional, Mushiroda, T, additional, Kamatani, N, additional, Goldspiel, BR, additional, Phillips, EJ, additional, Klein, TE, additional, and Lee, MTM, additional
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- 2015
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6. Primary immunodeficiency mutation databases
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Vihinen, M., Arredondo-Vega, Fx, Casanova, Jl, Etzioni, A., Giliani, S., Hammarstrom, L., Hershfield, Ms, Heyworth, Pg, Hsu, Ap, Lahdesmaki, A., Lappalainen, I., Notarangelo, Ld, Puck, Jm, Reith, W., Roos, D., Schumacher, Rf, Schwarz, K., Vezzoni, P., Villa, A., Valiaho, J., and C. I. Edvard SMITH
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Databases, Factual ,Genotype ,Models, Genetic ,Immunologic Deficiency Syndromes/ genetics ,Immunologic Deficiency Syndromes ,Mutation, Missense ,Chromosome Mapping ,ddc:616.07 ,Phenotype ,Mutation ,Humans ,CpG Islands ,Alleles - Abstract
Primary immunodeficiencies are intrinsic defects of immune systems. Mutations in a large number of cellular functions can lead to impaired immune responses. More than 80 primary immunodeficiencies are known to date. During the last years genes for several of these disorders have been identified. Here, mutation information for 23 genes affected in 14 immunodefects is presented. The proteins produced are employed in widely diverse functions, such as signal transduction, cell surface receptors, nucleotide metabolism, gene diversification, transcription factors, and phagocytosis. Altogether, the genetic defect of 2,140 families has been determined. Diseases with X-chromosomal origin constitute about 70% of all the cases, presumably due to full penetrance and because the single affected allele causes the phenotype. All types of mutations have been identified; missense mutations are the most common mutation type, and truncation is the most common effect on the protein level. Mutational hotspots in many disorders appear in CPG dinucleotides. The mutation data for the majority of diseases are distributed on the Internet with a special database management system, MUTbase. Despite large numbers of mutations, it has not been possible to make genotype-phenotype correlations for many of the diseases.
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- 2000
7. Seven novel mutations in the adenosine deaminase (ADA) gene in patients with severe and delayed onset combined immunodeficiency: G74C, V129M, G140E, R149W, Q199P, 462delG, and E337del
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Arredondo-Vega, FX, primary, Santisteban, I, additional, Notarangelo, LD, additional, Dahr, J. El, additional, Buckley, R, additional, Roifman, C, additional, Conley, ME, additional, and Hershfield, MS, additional
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- 1998
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8. Antibody responses to bacteriophage phi X174 in patients with adenosine deaminase deficiency
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Ochs, HD, primary, Buckley, RH, additional, Kobayashi, RH, additional, Kobayashi, AL, additional, Sorensen, RU, additional, Douglas, SD, additional, Hamilton, BL, additional, and Hershfield, MS, additional
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- 1992
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9. Reassessing serum urate targets in the management of refractory gout: can you go too low?
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Hershfield MS and Hershfield, Michael S
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- 2009
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10. CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells
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Kurtzberg, J, Waldmann, TA, Davey, MP, Bigner, SH, Moore, JO, Hershfield, MS, and Haynes, BF
- Abstract
Following our initial observation of in vivo conversion of CD7+, CD4-, CD8- acute lymphoblastic leukemia (ALL) cells from lymphoid to myeloid lineages (Proc Natl Acad Sci (USA) 81:253, 1984) we have studied eight additional cases of ALL with this leukemic cell phenotype. The CD7+, CD4-, CD8- phenotype was associated with a distinct clinical entity with those affected predominantly male (either less than 35 years or greater than 65 years of age), with frequent mediastinal and/or thymic masses, skin and CNS disease, high peripheral WBC counts, and bone marrow blasts that were morphologically L1 or not ascribable to a specific lineage. These patients did not respond to conventional chemotherapeutic regimens for either acute lymphoid or myeloid leukemias. No common karyotype or T-cell gene rearrangement pattern could be defined. Importantly, seven of eight patient's leukemic cells studied were capable of multilineage (myeloid, erythroid, monocytoid, megakaryocytoid, and lymphoid) differentiation in vitro. Data is presented suggesting that CD7+, CD4-, CD8- leukemias, in many instances, are leukemias of immature hematopoietic cells. The development of novel therapeutic approaches to this form of leukemia will be necessary to alter its poor prognosis.
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- 1989
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11. 277 The use of bovine polyethylene glycol-modified adenosine deaminase (PEG-ADA) in correcting the immunodeficiency in a child with severe combined immunodeficiency-adenosine deaminase deficiency (SCID-ADA[ − ])
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Kobayashi, AD, primary, Kobayashi, RH, additional, Schiff, RI, additional, Claassen, J, additional, and Hershfield, MS, additional
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- 1988
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12. Cerebral lymphoma in an adenosine deaminase-deficient patient with severe combined immunodeficiency receiving polyethylene glycol-conjugated adenosine deaminase.
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Kaufman DA, Hershfield MS, Bocchini JA, Moissidis IJ, Jeroudi M, and Bahna SL
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Polyethylene glycol--conjugated adenosine deaminase (PEG-ADA) provides an alternate therapy to mismatched stem cell transplantation for patients with ADA-deficient severe combined immunodeficiency. Although replacement therapy with PEG-ADA is effective in preventing infections, immune function does not return to normal, and most patients remain lymphopenic. Information is limited regarding the prognosis of patients on long-term ADA-replacement therapy. Here we present a case of a 10-year-old child who was diagnosed with ADA-severe combined immunodeficiency at 4 weeks of age after contracting pneumonia. Treatment with PEG-ADA was begun, the biochemical markers of ADA deficiency normalized, and his clinical progress was very good without significant infections. At 10 years of age, after presenting with headaches and cranial nerve deficits, he was diagnosed with Epstein-Barr virus--positive malignant brain lymphoma. It did not respond to various regimens of aggressive chemotherapy, and the patient expired 5 months later. We speculate that in this patient the immunologic surveillance by T cells may have been defective with respect to elimination of Epstein-Barr virus--infected cells, hence the formation of neoplasm. The possible mechanisms underlying such pathology are reviewed. [ABSTRACT FROM AUTHOR]
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- 2005
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13. Successful Long-Term Enzyme Replacement Therapy in a Patient with Delayed-Onset ADA Deficiency.
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Toskov V, Bali P, Hershfield MS, Ehl S, and Speckmann C
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- Humans, Treatment Outcome, Male, Female, Mutation genetics, Severe Combined Immunodeficiency, Enzyme Replacement Therapy methods, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Agammaglobulinemia drug therapy, Agammaglobulinemia therapy, Agammaglobulinemia genetics
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- 2024
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14. Evolving spectrum of adenosine deaminase (ADA) deficiency: Assessing genotype pathogenicity according to expressed ADA activity of 46 variants.
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Santisteban I, Arredondo-Vega FX, Bali P, Dalgic B, Lee HH, Kim M, Hermanson J, Tarrant TK, and Hershfield MS
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Background: Deficiency of adenosine deaminase (ADA or ADA1) has broad clinical and genetic heterogeneity. Screening techniques can identify asymptomatic infants whose phenotype and prognosis are indeterminate, and who may carry ADA variants of unknown significance., Objective: We systematically assessed the pathogenic potential of rare ADA missense variants to better define the relationship of genotype to red blood cell (RBC) total deoxyadenosine nucleotide (dAXP) content and to phenotype., Methods: We expressed 46 ADA missense variants in the ADA-deficient SØ3834 strain of Escherichia coli and defined genotype categories (GCs) ranked I to IV by increasing expressed ADA activity. We assessed relationships among GC rank, RBC dAXP, and phenotype in 58 reference patients with 50 different genotypes. We used our GC ranking system to benchmark AlphaMissense for predicting variant pathogenicity, and we used a minigene assay to identify exonic splicing variants in ADA exon 9., Results: The 46 missense variants expressed ∼0.001% to ∼70% of wild-type ADA activity (40% had <0.05% of wild-type ADA activity and 50% expressed >1%). RBC dAXP ranged from undetectable to >75% of total adenine nucleotides and correlated well with phenotype. Both RBC dAXP and clinical severity were inversely related to total ADA activity expressed by both inherited variants. Our GC scoring system performed better than AlphaMissense in assessing variant pathogenicity, particularly for less deleterious variants., Conclusion: For ADA deficiency, pathogenicity is a continuum and conditional, depending on the total ADA activity contributed by both inherited variants as indicated by GC rank. However, in patients with indeterminate phenotype identified by screening, RBC dAXP measured at diagnosis may have greater prognostic value than GC rank., Competing Interests: Disclosure statement Supported in part by grant DK20902 from the National Institutes of Health as well as grants from Enzon, Sigma-Tau Pharmaceuticals, Leadiant BioSciences, and Chiesi USA. Disclosure of potential conflict of interest: M. S. Hershfield and T. K. Tarrant have received grant support from Chiesi USA and have served as consultants. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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15. Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency.
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Hicks ED, Hall G, Hershfield MS, Tarrant TK, Bali P, Sleasman JW, Buckley RH, and Mousallem T
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- Animals, Female, Humans, Infant, Infant, Newborn, Male, Immune Reconstitution, Recombinant Proteins therapeutic use, Treatment Outcome, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Agammaglobulinemia therapy, Enzyme Replacement Therapy, Severe Combined Immunodeficiency therapy
- Abstract
Purpose: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi., Methods: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data., Results: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred., Conclusion: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data., (© 2024. The Author(s).)
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- 2024
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16. Comparison of disease phenotypes and mechanistic insight on causal variants in patients with DADA2.
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Chen L, Mamutova A, Kozlova A, Latysheva E, Evgeny F, Latysheva T, Savostyanov K, Pushkov A, Zhanin I, Raykina E, Kurnikova M, Mersiyanova I, Platt CD, Jee H, Brodeur K, Du Y, Liu M, Weiss A, Schulert GS, Rodriguez-Smith J, Hershfield MS, Aksentijevich I, Zhou Q, Nigrovic PA, Shcherbina A, Alexeeva E, and Lee PY
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- Humans, Intercellular Signaling Peptides and Proteins genetics, Phenotype, Mutation, Adenosine Deaminase genetics, Vasculitis
- Abstract
Background: Deficiency of adenosine deaminase 2 (DADA2) results in heterogeneous manifestations including systemic vasculitis and red cell aplasia. The basis of different disease phenotypes remains incompletely defined., Objective: We sought to further delineate disease phenotypes in DADA2 and define the mechanistic basis of ADA2 variants., Methods: We analyzed the clinical features and ADA2 variants in 33 patients with DADA2. We compared the transcriptomic profile of 14 patients by bulk RNA sequencing. ADA2 variants were expressed experimentally to determine impact on protein production, trafficking, release, and enzymatic function., Results: Transcriptomic analysis of PBMCs from DADA2 patients with the vasculitis phenotype or pure red cell aplasia phenotype exhibited similar upregulation of TNF, type I interferon, and type II interferon signaling pathways compared with healthy controls. These pathways were also activated in 3 asymptomatic individuals with DADA2. Analysis of ADA2 variants, including 7 novel variants, showed different mechanisms of functional disruption including (1) unstable transcript leading to RNA degradation; (2) impairment of ADA2 secretion because of retention in the endoplasmic reticulum; (3) normal expression and secretion of ADA2 that lacks enzymatic function; and (4) disruption of the N-terminal signal peptide leading to cytoplasmic localization of unglycosylated protein., Conclusions: Transcriptomic signatures of inflammation are observed in patients with different disease phenotypes, including some asymptomatic individuals. Disease-associated ADA2 variants affect protein function by multiple mechanisms, which may contribute to the clinical heterogeneity of DADA2., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
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- 2023
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17. Long-Term Immune Reconstitution in ADA-Deficient Patients Treated With Elapegademase: A Real-World Experience.
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Murguia-Favela L, Suresh S, Wright NAM, Alvi S, Tehseen S, Hernandez-Trujillo V, Seroogy CM, Haddad E, Nieves D, Hershfield MS, Walter JE, Pettiford L, Kamani NR, Keller MD, Pham-Huy A, and Grunebaum E
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- Infant, Humans, Animals, Cattle, Adenosine Deaminase therapeutic use, Immune Reconstitution, Severe Combined Immunodeficiency therapy
- Abstract
Background: ADAGEN, a bovine-based enzyme replacement therapy (ERT), has been used to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In 2018, ADAGEN was replaced by REVCOVI (elapegademase), a modified bovine recombinant protein., Objective: To determine the real-life long-term benefits of REVCOVI in ADA-SCID., Methods: Data on ERT, infectious and noninfectious complications, and metabolic and immune evaluations were collected from 17 patients with ADA-SCID treated for 6 months or more with REVCOVI., Results: Eleven patients had previously received ADAGEN for 16 to 324 months, whereas 6 patients were ERT-naive. REVCOVI was administered twice weekly at 0.4 mg/kg/wk in ERT-naive patients, whereas patients transitioning to REVCOVI from ADAGEN typically continued at the same frequency and equivalent dosing as ADAGEN, resulting in a significantly lower (P = .007) total REVCOVI dose in the transitioning group. REVCOVI treatment in the ERT-naive group led to the resolution of many clinical and laboratory complications of ADA deficiency, whereas there were no new adverse effects among the transitioning patients. REVCOVI treatment increased plasma ADA activity and decreased dAXP (which included deoxyadenosine mono-, di-, and tri phosphate) among most patients, effects that persisted throughout the 7- to 37-month treatment periods, except in 2 patients with incomplete adherence. Among some patients, after 0.5 to 6 months, injection frequency was reduced to once a week, while maintaining adequate metabolic profiles. All ERT-naive infants treated with REVCOVI demonstrated an increase in the number of CD4
+ T and CD19+ B cells, although these counts remained stable but lower than normal in most transitioning patients., Conclusions: REVCOVI is effective for the management of ADA-SCID., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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18. Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.
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Lee PY, Davidson BA, Abraham RS, Alter B, Arostegui JI, Bell K, Belot A, Bergerson JRE, Bernard TJ, Brogan PA, Berkun Y, Deuitch NT, Dimitrova D, Georgin-Lavialle SA, Gattorno M, Grimbacher B, Hashem H, Hershfield MS, Ichord RN, Izawa K, Kanakry JA, Khubchandani RP, Klouwer FCC, Luton EA, Man AW, Meyts I, Van Montfrans JM, Ozen S, Saarela J, Santo GC, Sharma A, Soldatos A, Sparks R, Torgerson TR, Uriarte IL, Youngstein TAB, Zhou Q, Aksentijevich I, Kastner DL, Chambers EP, and Ombrello AK
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- Phenotype, Heterozygote, Adenosine Deaminase genetics, Intercellular Signaling Peptides and Proteins
- Abstract
Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management., Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2., Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence., Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined., Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.
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- 2023
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19. Case Report: Deficiency of Adenosine Deaminase 2 (DADA2) as a Cause of Brainstem Stroke in a 3-Year-Old Girl and the Importance of Early Fast-Track Genetic Diagnostics to Influence Therapy.
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Gburek-Augustat J, Platzer K, Schumann I, Starke S, Hershfield MS, Sorge I, and Merkenschlager A
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- Child, Female, Humans, Child, Preschool, Intercellular Signaling Peptides and Proteins genetics, Mutation, Adenosine Deaminase genetics, Brain Stem Infarctions
- Abstract
Deficiency of adenosine deaminase 2 (DADA2) is a rare Mendelian, autoinflammatory multiorgan disease. We report the case of a 3.8-year-old female patient who was admitted with an acute brainstem stroke and was diagnosed with DADA2 by early initiation of exome sequencing. We recommend that DADA2 and a genetic workup should be taken into account, when evaluating strokes in children even if no other than neurological symptoms are evident., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2022
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20. Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency.
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Barzaghi F, Cicalese MP, Zoccolillo M, Brigida I, Barcella M, Merelli I, Sartirana C, Zanussi M, Calbi V, Bernardo ME, Tucci F, Migliavacca M, Giglio F, Doglio M, Canarutto D, Ferrua F, Consiglieri G, Prunotto G, Saettini F, Bonanomi S, Rovere-Querini P, Di Colo G, Jofra T, Fousteri G, Penco F, Gattorno M, Hershfield MS, Bongiovanni L, Ponzoni M, Marktel S, Milani R, Peccatori J, Ciceri F, Mortellaro A, and Aiuti A
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- Adenosine Deaminase genetics, Granulocyte Colony-Stimulating Factor, Humans, Intercellular Signaling Peptides and Proteins, Severe Combined Immunodeficiency, Tumor Necrosis Factor Inhibitors, Twins, Monozygotic genetics, Agammaglobulinemia diagnosis, Agammaglobulinemia genetics, Neutropenia, Polyarteritis Nodosa
- Abstract
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal ADA2 allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barzaghi, Cicalese, Zoccolillo, Brigida, Barcella, Merelli, Sartirana, Zanussi, Calbi, Bernardo, Tucci, Migliavacca, Giglio, Doglio, Canarutto, Ferrua, Consiglieri, Prunotto, Saettini, Bonanomi, Rovere-Querini, Di Colo, Jofra, Fousteri, Penco, Gattorno, Hershfield, Bongiovanni, Ponzoni, Marktel, Milani, Peccatori, Ciceri, Mortellaro and Aiuti.)
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- 2022
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21. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC.
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Cuvelier GDE, Logan BR, Prockop SE, Buckley RH, Kuo CY, Griffith LM, Liu X, Yip A, Hershfield MS, Ayoub PG, Moore TB, Dorsey MJ, O'Reilly RJ, Kapoor N, Pai SY, Kapadia M, Ebens CL, Forbes Satter LR, Burroughs LM, Petrovic A, Chellapandian D, Heimall J, Shyr DC, Rayes A, Bednarski JJ, Chandra S, Chandrakasan S, Gillio AP, Madden L, Quigg TC, Caywood EH, Dávila Saldaña BJ, DeSantes K, Eissa H, Goldman FD, Rozmus J, Shah AJ, Vander Lugt MT, Thakar MS, Parrott RE, Martinez C, Leiding JW, Torgerson TR, Pulsipher MA, Notarangelo LD, Cowan MJ, Dvorak CC, Haddad E, Puck JM, and Kohn DB
- Subjects
- Adenosine Deaminase, Child, Preschool, Humans, Infant, Infant, Newborn, Agammaglobulinemia genetics, Hematopoietic Stem Cell Transplantation, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy
- Abstract
Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.
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- 2022
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22. Common Variable Immunodeficiency in a Carrier of the ADA2 R169Q Variant: Coincidence or Causality?
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Moi L, Schnider C, Riccio O, Hershfield MS, and Candotti F
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- Humans, Phenotype, Adenosine Deaminase genetics, Common Variable Immunodeficiency diagnosis, Common Variable Immunodeficiency genetics, Intercellular Signaling Peptides and Proteins genetics
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- 2022
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23. Polyethylene Glycol-Like Brush Polymer Conjugate of a Protein Drug Does Not Induce an Antipolymer Immune Response and Has Enhanced Pharmacokinetics than Its Polyethylene Glycol Counterpart.
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Ozer I, Kelly G, Gu R, Li X, Zakharov N, Sirohi P, Nair SK, Collier JH, Hershfield MS, Hucknall AM, and Chilkoti A
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- Antibodies metabolism, Antigens therapeutic use, Humans, Immunity, Polyethylene Glycols pharmacokinetics, Polyethylene Glycols therapeutic use, Polymers therapeutic use, Gout drug therapy, Urate Oxidase pharmacokinetics, Urate Oxidase therapeutic use
- Abstract
Protein therapeutics, except for antibodies, have a short plasma half-life and poor stability in circulation. Covalent coupling of polyethylene glycol (PEG) to protein drugs addresses this limitation. However, unlike previously thought, PEG is immunogenic. In addition to induced PEG antibodies, ≈70% of the US population has pre-existing anti-PEG antibodies. Both induced and preexisting anti-PEG antibodies result in accelerated drug clearance, reduced clinical efficacy, and severe hypersensitivity reactions that have limited the clinical utility of uricase, an enzyme drug for treatment for refractory gout that is decorated with a PEG corona. Here, the authors synthesize a poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) conjugate of uricase that decorates the protein with multiple polymer chains to create a corona to solve these problems. The resulting uricase-POEGMA is well-defined, has high bioactivity, and outperforms its PEG counterparts in its pharmacokinetics (PK). Furthermore, the conjugate does not induce anti-POEGMA antibodies and is not recognized by anti-PEG antibodies. These findings suggest that POEGMA conjugation may provide a solution to the immunogenicity and antigenicity limitations of PEG while improving upon its PK benefits. These results transcend uricase and can be applied to other PEGylated therapeutics and the broader class of biologics with suboptimal PK., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)
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- 2022
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24. Response to: 'Total adenosine deaminase highly correlated with adenosine deaminase 2 activity in serum' by Gao et al .
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Lee PY, Huang Z, Hershfield MS, and Nigrovic PA
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- Biomarkers, Humans, Adenosine Deaminase genetics
- Abstract
Competing Interests: Competing interests: None declared.
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- 2022
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25. Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach.
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Jee H, Huang Z, Baxter S, Huang Y, Taylor ML, Henderson LA, Rosenzweig S, Sharma A, Chambers EP, Hershfield MS, Zhou Q, Dedeoglu F, Aksentijevich I, Nigrovic PA, O'Donnell-Luria A, and Lee PY
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase deficiency, Algorithms, Genetic Predisposition to Disease, Genetic Variation, HEK293 Cells, Humans, Immune System Diseases genetics, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins deficiency, Adenosine Deaminase genetics, Intercellular Signaling Peptides and Proteins genetics
- Abstract
Background: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown., Objective: We aimed to characterize the functional impact and carrier frequency of ADA2 variants., Methods: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants., Results: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals., Conclusions: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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26. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.
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Reinhardt B, Habib O, Shaw KL, Garabedian E, Carbonaro-Sarracino DA, Terrazas D, Fernandez BC, De Oliveira S, Moore TB, Ikeda AK, Engel BC, Podsakoff GM, Hollis RP, Fernandes A, Jackson C, Shupien S, Mishra S, Davila A, Mottahedeh J, Vitomirov A, Meng W, Rosenfeld AM, Roche AM, Hokama P, Reddy S, Everett J, Wang X, Luning Prak ET, Cornetta K, Hershfield MS, Sokolic R, De Ravin SS, Malech HL, Bushman FD, Candotti F, and Kohn DB
- Subjects
- Adenosine Deaminase genetics, Adolescent, Agammaglobulinemia genetics, Child, Child, Preschool, Follow-Up Studies, Hematopoietic Stem Cell Transplantation methods, Humans, Infant, Severe Combined Immunodeficiency genetics, Transplantation, Autologous methods, Treatment Outcome, Agammaglobulinemia therapy, Genetic Therapy methods, Severe Combined Immunodeficiency therapy
- Abstract
Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)-ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508., (© 2021 by The American Society of Hematology.)
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- 2021
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27. Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy.
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Baloh CH, Borkar SA, Chang KF, Yao J, Hershfield MS, Parikh SH, Kohn DB, Goodenow MM, Sleasman JW, and Yin L
- Subjects
- Adenosine Deaminase deficiency, Adenosine Deaminase therapeutic use, Agammaglobulinemia therapy, Enzyme Replacement Therapy, Female, Genetic Therapy, Humans, Infant, Lymphocyte Count, Severe Combined Immunodeficiency therapy, Agammaglobulinemia immunology, Immunoglobulin Heavy Chains immunology, Severe Combined Immunodeficiency immunology
- Abstract
Purpose: Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) through an accumulation of toxic metabolites within lymphocytes. Recently, ADA deficiency has been successfully treated using lentiviral-transduced autologous CD34+ cells carrying the ADA gene. T and B cell function appears to be fully restored, but in many patients' B cell numbers remain low, and assessments of the immunoglobulin heavy (IgHV) repertoire following gene therapy are lacking., Methods: We performed deep sequencing of IgHV repertoire in peripheral blood lymphocytes from a child following lentivirus-based gene therapy for ADA deficiency and compared to the IgHV repertoire in healthy infants and adults., Results: After gene therapy, Ig diversity increased over time as evidenced by V, D, and J gene usage, N-additions, CDR3 length, extent of somatic hypermutation, and Ig class switching. There was the emergence of predominant IgHM, IgHG, and IgHA CDR3 lengths after gene therapy indicating successful oligoclonal expansion in response to antigens. This provides proof of concept for the feasibility and utility of molecular monitoring in following B cell reconstitution following gene therapy for ADA deficiency., Conclusion: Based on deep sequencing, gene therapy resulted in an IgHV repertoire with molecular diversity similar to healthy infants., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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28. ADA2 deficiency (DADA2) associated with Evans syndrome and a severe ADA2 genotype.
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Ferriani MPL, Valera ET, de Sousa GR, Sandrin-Garcia P, de Moura RR, Hershfield MS, and de Carvalho LM
- Subjects
- Agammaglobulinemia complications, Agammaglobulinemia drug therapy, Anemia, Hemolytic, Autoimmune complications, Anemia, Hemolytic, Autoimmune drug therapy, Antirheumatic Agents therapeutic use, Child, Etanercept therapeutic use, Female, Glucocorticoids therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Immunologic Factors therapeutic use, Mutation, Missense, Pedigree, Sequence Deletion, Severe Combined Immunodeficiency complications, Severe Combined Immunodeficiency drug therapy, Thrombocytopenia complications, Thrombocytopenia drug therapy, Adenosine Deaminase genetics, Agammaglobulinemia genetics, Anemia, Hemolytic, Autoimmune genetics, Intercellular Signaling Peptides and Proteins genetics, Severe Combined Immunodeficiency genetics, Thrombocytopenia genetics
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- 2021
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29. Uncontrolled Epstein-Barr Virus as an Atypical Presentation of Deficiency in ADA2 (DADA2).
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Brooks JP, Rice AJ, Ji W, Lanahan SM, Konstantino M, Dara J, Hershfield MS, Cruickshank A, Dokmeci E, Lakhani S, and Lucas CL
- Subjects
- Adenosine Deaminase blood, Antiviral Agents therapeutic use, Biomarkers, Biopsy, Child, DNA Mutational Analysis, Disease Management, Disease Susceptibility, Epstein-Barr Virus Infections drug therapy, Female, Hematopoietic Stem Cell Transplantation, Humans, Intercellular Signaling Peptides and Proteins blood, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency therapy, Siblings, Symptom Assessment, Tomography, X-Ray Computed, Treatment Outcome, Exome Sequencing, Adenosine Deaminase deficiency, Epstein-Barr Virus Infections diagnosis, Epstein-Barr Virus Infections etiology, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency complications, Severe Combined Immunodeficiency genetics
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- 2021
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30. Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.
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Suri D, Rawat A, Jindal AK, Vignesh P, Gupta A, Pilania RK, Joshi V, Arora K, Kumrah R, Anjani G, Aggarwal A, Phadke S, Aboobacker FN, George B, Edison ES, Desai M, Taur P, Gowri V, Pandrowala AA, Bhattad S, Kanakia S, Gottorno M, Ceccherini I, Almeida de Jesus A, Goldbach-Mansky R, Hershfield MS, and Singh S
- Subjects
- Female, Hereditary Autoinflammatory Diseases diagnosis, Hereditary Autoinflammatory Diseases therapy, Humans, Male, Hereditary Autoinflammatory Diseases complications
- Abstract
Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Results: Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 ( DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 ( NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG
2 -associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Suri, Rawat, Jindal, Vignesh, Gupta, Pilania, Joshi, Arora, Kumrah, Anjani, Aggarwal, Phadke, Aboobacker, George, Edison, Desai, Taur, Gowri, Pandrowala, Bhattad, Kanakia, Gottorno, Ceccherini, Almeida de Jesus, Goldbach-Mansky, Hershfield and Singh.)- Published
- 2021
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31. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.
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Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, Bhatia P, Sharma V, Bhattad S, Chengappa KG, Gupta V, Misra DP, Chavan PP, Malaviya S, Dudam R, Sharma B, Kumar S, Bhojwani R, Gupta P, Agarwal V, Sharma K, Singhal M, Rathi M, Nada R, Minz RW, Chaturvedi V, Aggarwal A, Handa R, Grossi A, Gattorno M, Huang Z, Wang J, Jois R, Negi VS, Khubchandani R, Jain S, Arostegui JI, Chambers EP, Hershfield MS, Aksentijevich I, Zhou Q, and Lee PY
- Subjects
- Adenosine Deaminase genetics, Adenosine Deaminase metabolism, Adolescent, Adult, Agammaglobulinemia diagnosis, Agammaglobulinemia drug therapy, Agammaglobulinemia genetics, Age of Onset, Anemia physiopathology, Child, Child, Preschool, Delayed Diagnosis, Female, Glucocorticoids therapeutic use, Hemorrhage physiopathology, Humans, India, Infant, Infarction physiopathology, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Leukopenia physiopathology, Lung Diseases physiopathology, Male, Myocarditis physiopathology, Pancreatic Diseases physiopathology, Retrospective Studies, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency drug therapy, Severe Combined Immunodeficiency genetics, Stroke physiopathology, Treatment Outcome, Tumor Necrosis Factor Inhibitors therapeutic use, Vasculitis physiopathology, Young Adult, Agammaglobulinemia physiopathology, Gastrointestinal Diseases physiopathology, Hematologic Diseases physiopathology, Kidney Diseases physiopathology, Nervous System Diseases physiopathology, Severe Combined Immunodeficiency physiopathology
- Abstract
Objective: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India., Methods: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects., Results: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported., Conclusion: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults., (© 2020, American College of Rheumatology.)
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- 2021
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32. Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.
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Lee PY, Schulert GS, Canna SW, Huang Y, Sundel J, Li Y, Hoyt KJ, Blaustein RB, Wactor A, Do T, Halyabar O, Chang MH, Dedeoglu F, Case SM, Meidan E, Lo MS, Sundel RP, Richardson ET, Newburger JW, Hershfield MS, Son MB, Henderson LA, and Nigrovic PA
- Subjects
- Adolescent, Adult, Arthritis, Juvenile complications, Biomarkers blood, Blood Sedimentation, C-Reactive Protein analysis, Chemokine CXCL9 blood, Child, Dermatomyositis blood, Dermatomyositis immunology, Female, Ferritins blood, Humans, Interleukin-18 blood, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic immunology, Macrophage Activation Syndrome immunology, Male, Mucocutaneous Lymph Node Syndrome blood, Mucocutaneous Lymph Node Syndrome immunology, Reference Values, Sensitivity and Specificity, Adenosine Deaminase blood, Arthritis, Juvenile blood, Intercellular Signaling Peptides and Proteins blood, Macrophage Activation Syndrome diagnosis
- Abstract
Objective: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS., Methods: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis., Results: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes., Conclusions: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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33. Morbidity in an adenosine deaminase-deficient patient during 27 years of enzyme replacement therapy.
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Grunebaum E, Reid B, Naqvi A, Hershfield MS, Kim VH, Muller MP, Hicks LK, Lee E, Betschel S, and Roifman CM
- Subjects
- Adenosine Deaminase therapeutic use, Adult, Agammaglobulinemia epidemiology, Female, Humans, Morbidity, Severe Combined Immunodeficiency epidemiology, Adenosine Deaminase deficiency, Agammaglobulinemia drug therapy, Enzyme Replacement Therapy, Severe Combined Immunodeficiency drug therapy
- Abstract
Introduction: Adenosine deaminase (ADA) deficiency causes severe immunodeficiency that is lethal in infancy. Enzyme replacement therapy (ERT) can improve the metabolic, immune and non-immune abnormalities in patients prior to transplantation, however, its benefits over extended periods are not well characterized. We describe a 28-year-old female who received ERT for 27 years. She suffered from EBV negative B cell lymphoma of the hip at 14 years of age and Guillian-Barre Syndrome 2 years later. At 22 years of age, she experienced a gastrointestinal infection with Mycobacterium genavense. At 26 years of age, lymphoma reoccurred with multiple liver lesions followed by Mycobacterium genavense infection with dissemination to the brain. Throughout this period, ADA activity in the plasma was within the therapeutic range. Repeated evaluations demonstrated very low lymphocyte counts and impaired T cell function., Conclusions: ERT might be insufficient to maintain normal immunity over extended periods in some ADA-deficient patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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34. Unreported Missense Mutation in the Dimerization Domain of ADA2 Leads to ADA2 Deficiency Associated with Severe Oral Ulcers and Neutropenia in a Female Somalian Patient-Addendum to the Genotype-Phenotype Puzzle.
- Author
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Göschl L, Winkler S, Dmytrus J, Heredia RJ, Lagler H, Ramharter M, Scheinecker C, Bonelli M, Schmetterer K, Pickl WF, Grabmeier-Pfistershammer K, Hershfield MS, Boztug K, Förster-Waldl E, and Gualdoni GA
- Subjects
- Agammaglobulinemia genetics, Dimerization, Female, Genotype, Humans, Phenotype, Severe Combined Immunodeficiency genetics, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Intercellular Signaling Peptides and Proteins deficiency, Intercellular Signaling Peptides and Proteins genetics, Mutation, Missense genetics, Neutropenia genetics, Oral Ulcer genetics
- Published
- 2020
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35. Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.
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Bursill D, Taylor WJ, Terkeltaub R, Abhishek A, So AK, Vargas-Santos AB, Gaffo AL, Rosenthal A, Tausche AK, Reginato A, Manger B, Sciré C, Pineda C, van Durme C, Lin CT, Yin C, Albert DA, Biernat-Kaluza E, Roddy E, Pascual E, Becce F, Perez-Ruiz F, Sivera F, Lioté F, Schett G, Nuki G, Filippou G, McCarthy G, da Rocha Castelar Pinheiro G, Ea HK, Tupinambá HA, Yamanaka H, Choi HK, Mackay J, ODell JR, Vázquez Mellado J, Singh JA, Fitzgerald JD, Jacobsson LTH, Joosten L, Harrold LR, Stamp L, Andrés M, Gutierrez M, Kuwabara M, Dehlin M, Janssen M, Doherty M, Hershfield MS, Pillinger M, Edwards NL, Schlesinger N, Kumar N, Slot O, Ottaviani S, Richette P, MacMullan PA, Chapman PT, Lipsky PE, Robinson P, Khanna PP, Gancheva RN, Grainger R, Johnson RJ, Te Kampe R, Keenan RT, Tedeschi SK, Kim S, Choi SJ, Fields TR, Bardin T, Uhlig T, Jansen T, Merriman T, Pascart T, Neogi T, Klück V, Louthrenoo W, and Dalbeth N
- Subjects
- Consensus, Humans, Gout classification, Hyperuricemia classification, Terminology as Topic
- Abstract
Objective: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout., Methods: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions., Results: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus)., Conclusion: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice., Competing Interests: Competing interests: AKT has received speaking fees and honoraria for advisory boards from Berlin Chemie Menarini, Novartis, Grünenthal and AstraZeneca. JAS has received consultant fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Medscape, WebMD, the National Institutes of Health and the American College of Rheumatology. JAS owns stock options in Amarin pharmaceuticals and Viking therapeutics. JAS is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies. JAS is a member of the Veterans Affairs Rheumatology Field Advisory Committee. JAS is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. JAS previously served as a member of the following committees: member, the American College of Rheumatology's (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, the Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and the co-chair of the ACR Criteria and Response Criteria subcommittee. ND has received speaking fees from Pfizer, Horizon, Janssen, and AbbVie, consulting fees from Horizon, AstraZeneca, Dyve Biosciences, Hengrui, and Kowa, and research funding from Amgen and AstraZeneca., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2019
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36. Homozygous Splice ADA2 Gene Mutation Causing ADA-2 Deficiency.
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Chong-Neto HJ, Segundo GRS, Bandeira M, Chong-Silva DC, Rosário CS, Riedi CA, Hershfield MS, Ochs H, Torgerson T, and Rosário NA
- Subjects
- Adenosine Deaminase genetics, Adenosine Deaminase immunology, Agammaglobulinemia diagnosis, Agammaglobulinemia immunology, Child, Female, Homozygote, Humans, Intercellular Signaling Peptides and Proteins deficiency, Loss of Function Mutation, Mutation, RNA Splicing genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency immunology, Adenosine Deaminase deficiency, Agammaglobulinemia genetics, Intercellular Signaling Peptides and Proteins genetics, RNA Splice Sites genetics, RNA Splicing immunology, Severe Combined Immunodeficiency genetics
- Published
- 2019
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37. Anti-PEG Antibodies Inhibit the Anticoagulant Activity of PEGylated Aptamers.
- Author
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Moreno A, Pitoc GA, Ganson NJ, Layzer JM, Hershfield MS, Tarantal AF, and Sullenger BA
- Subjects
- Animals, Antibodies blood, Antigen-Antibody Reactions, Aptamers, Nucleotide administration & dosage, Aptamers, Nucleotide chemistry, Chlorides toxicity, Disease Models, Animal, Factor IXa metabolism, Female, Ferric Compounds toxicity, Humans, Macaca mulatta, Mice, Mice, Inbred C57BL, Partial Thromboplastin Time, Thrombosis chemically induced, Thrombosis drug therapy, Thrombosis pathology, Antibodies immunology, Anticoagulants chemistry, Aptamers, Nucleotide immunology, Polyethylene Glycols chemistry
- Abstract
Biopharmaceuticals have become increasingly attractive therapeutic agents and are often PEGylated to enhance their pharmacokinetics and reduce their immunogenicity. However, recent human clinical trials have demonstrated that administration of PEGylated compounds can evoke anti-PEG antibodies. Considering the ubiquity of PEG in commercial products and the presence of pre-existing anti-PEG antibodies in patients in large clinical trials evaluating a PEG-modified aptamer, we investigated how anti-PEG antibodies effect the therapeutic activities of PEGylated RNA aptamers. We demonstrate that anti-PEG antibodies can directly bind to and inhibit anticoagulant aptamer function in vitro and in vivo. Moreover, in parallel studies we detected the presence of anti-PEG antibodies in nonhuman primates after a single administration of a PEGylated aptamer. Our results suggest that anti-PEG antibodies can limit the activity of PEGylated drugs and potentially compromise the activity of otherwise effective therapeutic agents., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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38. Architectural Modification of Conformal PEG-Bottlebrush Coatings Minimizes Anti-PEG Antigenicity While Preserving Stealth Properties.
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Joh DY, Zimmers Z, Avlani M, Heggestad JT, Aydin HB, Ganson N, Kumar S, Fontes CM, Achar RK, Hershfield MS, Hucknall AM, and Chilkoti A
- Subjects
- Animals, Antibodies analysis, Antibodies metabolism, Mice, NIH 3T3 Cells, Prostheses and Implants, Serum Albumin, Bovine chemistry, Serum Albumin, Bovine metabolism, Surface Properties, Antigens chemistry, Antigens immunology, Antigens metabolism, Antigens ultrastructure, Coated Materials, Biocompatible adverse effects, Coated Materials, Biocompatible chemistry, Coated Materials, Biocompatible metabolism, Polyethylene Glycols chemistry, Polyethylene Glycols metabolism
- Abstract
Poly(ethylene glycol) (PEG), a linear polymer known for its "stealth" properties, is commonly used to passivate the surface of biomedical implants and devices, and it is conjugated to biologic drugs to improve their pharmacokinetics. However, its antigenicity is a growing concern. Here, the antigenicity of PEG is investigated when assembled in a poly(oligoethylene glycol) methacrylate (POEGMA) "bottlebrush" configuration on a planar surface. Using ethylene glycol (EG) repeat lengths of the POEGMA sidechains as a tunable parameter for optimization, POEGMA brushes with sidechain lengths of two and three EG repeats are identified as the optimal polymer architecture to minimize binding of anti-PEG antibodies (APAs), while retaining resistance to nonspecific binding by bovine serum albumin and cultured cells. Binding of backbone- versus endgroup-selective APAs to POEGMA brushes is further investigated, and finally the antigenicity of POEGMA coatings is assessed against APA-positive clinical plasma samples. These results are applied toward fabricating immunoassays on POEGMA surfaces with minimal reactivity toward APAs while retaining a low limit-of-detection for the analyte. Taken together, these results offer useful design concepts to reduce the antigenicity of polymer brush-based surface coatings used in applications involving human or animal matrices., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2019
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39. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency.
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Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, and Grunebaum E
- Subjects
- Adenosine Deaminase therapeutic use, Animals, Consensus, Enzyme Replacement Therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Severe Combined Immunodeficiency therapy
- Abstract
Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2019
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40. Gout, Hyperuricemia, and Crystal-Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout.
- Author
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Bursill D, Taylor WJ, Terkeltaub R, Kuwabara M, Merriman TR, Grainger R, Pineda C, Louthrenoo W, Edwards NL, Andrés M, Vargas-Santos AB, Roddy E, Pascart T, Lin CT, Perez-Ruiz F, Tedeschi SK, Kim SC, Harrold LR, McCarthy G, Kumar N, Chapman PT, Tausche AK, Vazquez-Mellado J, Gutierrez M, da Rocha Castelar-Pinheiro G, Richette P, Pascual E, Fisher MC, Burgos-Vargas R, Robinson PC, Singh JA, Jansen TL, Saag KG, Slot O, Uhlig T, Solomon DH, Keenan RT, Scire CA, Biernat-Kaluza E, Dehlin M, Nuki G, Schlesinger N, Janssen M, Stamp LK, Sivera F, Reginato AM, Jacobsson L, Lioté F, Ea HK, Rosenthal A, Bardin T, Choi HK, Hershfield MS, Czegley C, Choi SJ, and Dalbeth N
- Subjects
- Crystal Arthropathies classification, Gout classification, Humans, Hyperuricemia classification, Uric Acid analysis, Consensus, Crystal Arthropathies diagnosis, Delphi Technique, Gout diagnosis, Hyperuricemia diagnosis
- Abstract
Objective: The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout., Methods: Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting., Results: There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (≥80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used., Conclusion: Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout., (© 2018, American College of Rheumatology.)
- Published
- 2019
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41. ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation.
- Author
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Barzaghi F, Minniti F, Mauro M, Bortoli M, Balter R, Bonetti E, Zaccaron A, Vitale V, Omrani M, Zoccolillo M, Brigida I, Cicalese MP, Degano M, Hershfield MS, Aiuti A, Bondarenko AV, Chinello M, and Cesaro S
- Subjects
- Adenosine Deaminase immunology, Apoptosis drug effects, Apoptosis immunology, Autoimmune Lymphoproliferative Syndrome enzymology, Autoimmune Lymphoproliferative Syndrome immunology, Autoimmune Lymphoproliferative Syndrome pathology, Child, Preschool, Female, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Intercellular Signaling Peptides and Proteins immunology, Neutropenia enzymology, Neutropenia immunology, Neutropenia pathology, Neutropenia therapy, Transplantation, Homologous, fas Receptor immunology, Adenosine Deaminase deficiency, Autoimmune Lymphoproliferative Syndrome therapy, Hematopoietic Stem Cell Transplantation, Intercellular Signaling Peptides and Proteins deficiency, Transplantation Conditioning, Unrelated Donors
- Abstract
Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 ( CECR1 ) gene, currently named ADA2 . The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.
- Published
- 2019
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42. Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2.
- Author
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Lee PY, Huang Y, Zhou Q, Schnappauf O, Hershfield MS, Li Y, Ganson NJ, Sampaio Moura N, Delmonte OM, Stone SS, Rivkin MJ, Pai SY, Lyons T, Sundel RP, Hsu VW, Notarangelo LD, Aksentijevich I, and Nigrovic PA
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase genetics, Agammaglobulinemia blood, Child, Preschool, Female, Glycosylation, Humans, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins genetics, Mutation, Severe Combined Immunodeficiency blood, Adenosine Deaminase deficiency, Agammaglobulinemia genetics, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency genetics
- Published
- 2018
- Full Text
- View/download PDF
43. Hematopoietic Stem Cell Transplantation in ADA2 Deficiency: Early Restoration of ADA2 Enzyme Activity and Disease Relapse upon Drop of Donor Chimerism.
- Author
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Bucciol G, Delafontaine S, Segers H, Bossuyt X, Hershfield MS, Moens L, and Meyts I
- Subjects
- Autoimmunity genetics, Child, Preschool, Chimerism, Disease Progression, Enzyme Activation, Female, Humans, Infant, Male, Recurrence, Tissue Donors, Adenosine Deaminase genetics, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes therapy, Intercellular Signaling Peptides and Proteins genetics
- Published
- 2017
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- View/download PDF
44. Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders.
- Author
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Hashem H, Kelly SJ, Ganson NJ, and Hershfield MS
- Subjects
- Humans, Mutation, Phenotype, Adenosine Deaminase genetics, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins genetics, Polyarteritis Nodosa genetics, Rheumatic Diseases genetics
- Abstract
Purpose of Review: A new autoinflammatory disease, deficiency of adenosine deaminase 2 (DADA2), caused by mutations in the CECR1 gene, was first reported in 2014. This review aims to update progress in defining, treating, and understanding this multi-faceted disorder., Recent Findings: DADA2 was first described in patients with systemic inflammation, mild immune deficiency, and vasculopathy manifested as recurrent stroke or polyarteritis nodosa (PAN). More than 125 patients have now been reported, and the phenotype has expanded to include children and adults presenting primarily with pure red cell aplasia (PRCA), or with antibody deficiency. Age of onset and clinical severity vary widely, even among related patients, and are not clearly related to CECR1 genotype. Inflammatory features often respond to anti-TNF agents, but marrow failure and severe immune deficiency may require hematopoietic stem cell transplantation. ADA2 is expressed and secreted by monocytes and macrophages, but its biological function and the pathogenesis of DADA2 are uncertain and will remain an important area of research. Pre-clinical investigation of ADA2 replacement therapy and CECR1-directed gene therapy are warranted, but complicated by the absence of a suitable animal model.
- Published
- 2017
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45. A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol.
- Author
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Chang CJ, Chen CH, Chen BM, Su YC, Chen YT, Hershfield MS, Lee MM, Cheng TL, Chen YT, Roffler SR, and Wu JY
- Subjects
- Adult, Aged, Aged, 80 and over, Asian People genetics, China, Cohort Studies, Drug Hypersensitivity etiology, Drug Hypersensitivity immunology, Female, Genome-Wide Association Study, Humans, Immunoglobulin G immunology, Immunoglobulin M immunology, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Drug Hypersensitivity genetics, Polyethylene Glycols adverse effects
- Abstract
Conjugation of polyethylene glycol (PEG) to therapeutic molecules can improve bioavailability and therapeutic efficacy. However, some healthy individuals have pre-existing anti-PEG antibodies and certain patients develop anti-PEG antibody during treatment with PEGylated medicines, suggesting that genetics might play a role in PEG immunogenicity. Here we perform genome-wide association studies for anti-PEG IgM and IgG responses in Han Chinese with 177 and 140 individuals, defined as positive for anti-PEG IgM and IgG responses, respectively, and with 492 subjects without either anti-PEG IgM or IgG as controls. We validate the association results in the replication cohort, consisting of 211 and 192 subjects with anti-PEG IgM and anti-PEG IgG, respectively, and 596 controls. We identify the immunoglobulin heavy chain (IGH) locus to be associated with anti-PEG IgM response at genome-wide significance (P = 2.23 × 10
-22 ). Our findings may provide novel genetic markers for predicting the immunogenicity of PEG and efficacy of PEGylated therapeutics.Some individuals develop antibodies against the polyethylene glycol that is commonly used in therapeutic preparations. Here the authors conduct a GWAS in Han Chinese and find the IGH locus is associated with anti-PEG IgM.- Published
- 2017
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46. Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency.
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Ben-Ami T, Revel-Vilk S, Brooks R, Shaag A, Hershfield MS, Kelly SJ, Ganson NJ, Kfir-Erenfeld S, Weintraub M, Elpeleg O, Berkun Y, and Stepensky P
- Subjects
- Adenosine Deaminase genetics, Child, Child, Preschool, Female, Humans, Infant, Intercellular Signaling Peptides and Proteins genetics, Male, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Phenotype, Adenosine Deaminase deficiency, Intercellular Signaling Peptides and Proteins deficiency
- Abstract
Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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47. Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation.
- Author
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Hsu AP, West RR, Calvo KR, Cuellar-Rodriguez J, Parta M, Kelly SJ, Ganson NJ, Hershfield MS, Holland SM, and Hickstein DD
- Subjects
- Adenosine Deaminase genetics, Adolescent, Adult, Agammaglobulinemia genetics, Child, Child, Preschool, Codon, Nonsense, Diagnostic Errors, Female, Humans, Intercellular Signaling Peptides and Proteins genetics, Male, Severe Combined Immunodeficiency genetics, Transplantation, Haploidentical, Exome Sequencing, Young Adult, Adenosine Deaminase deficiency, Agammaglobulinemia diagnosis, Agammaglobulinemia therapy, GATA2 Transcription Factor deficiency, Hematopoietic Stem Cell Transplantation, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency therapy
- Published
- 2016
- Full Text
- View/download PDF
48. Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer.
- Author
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Ganson NJ, Povsic TJ, Sullenger BA, Alexander JH, Zelenkofske SL, Sailstad JM, Rusconi CP, and Hershfield MS
- Subjects
- Anticoagulants immunology, Aptamers, Nucleotide immunology, Drug Hypersensitivity diagnosis, Enzyme-Linked Immunosorbent Assay, Follow-Up Studies, Humans, Anticoagulants adverse effects, Aptamers, Nucleotide adverse effects, Drug Hypersensitivity immunology, Immunoglobulin G immunology, Polyethylene Glycols
- Published
- 2016
- Full Text
- View/download PDF
49. A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity.
- Author
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Qi Y, Simakova A, Ganson NJ, Li X, Luginbuhl KM, Özer I, Liu W, Hershfield MS, Matyjaszewski K, and Chilkoti A
- Abstract
The delivery of therapeutic peptides and proteins is often challenged by a short half-life, and thus the need for frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. Here, we demonstrate that a single subcutaneous injection of site-specific (C-terminal) conjugates of exendin-4 (exendin) - a therapeutic peptide that is clinically used to treat type 2 diabetes - and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) with precisely controlled molecular weights lowered blood glucose for up to 120 h in fed mice. Most notably, we show that an exendin-C-POEGMA conjugate with an average of 9 side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (PEG) antibodies than two FDA-approved PEGylated drugs, and that reducing the side-chain length to 3 EG repeats completely eliminates PEG antigenicity without compromising in vivo efficacy. Our findings establish the site-specific conjugation of POEGMA as a next-generation PEGylation technology for improving the pharmacological performance of traditional PEGylated drugs, whose safety and efficacy are hindered by pre-existing anti-PEG antibodies in patients., Competing Interests: Competing Financial Interests A.C. and Y.Q. have a pending patent on the sortase-catalyzed C-terminal polymer conjugation technology (WO 2014194244 A1). M.S.H. is a co-inventor of Pegloticase (Krystexxa®) and receives royalties from sales of Pegloticase, along with his employer, Duke University.
- Published
- 2016
- Full Text
- View/download PDF
50. A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient.
- Author
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Tartibi HM, Hershfield MS, and Bahna SL
- Subjects
- Follow-Up Studies, Humans, Infant, Male, Young Adult, Adenosine Deaminase deficiency, Adenosine Deaminase therapeutic use, Agammaglobulinemia drug therapy, Enzyme Replacement Therapy, Severe Combined Immunodeficiency drug therapy
- Abstract
Severe combined immunodeficiency (SCID) is a fatal childhood disease unless immune reconstitution is performed early in life, with either hematopoietic stem cell transplantation or gene therapy. One of its subtypes is caused by adenosine deaminase (ADA) enzyme deficiency, which leads to the accumulation of toxic metabolites that impair lymphocyte development and function. With the development of polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme replacement therapy, many ADA-deficient children with SCID who could not receive a hematopoietic stem cell transplantation or gene therapy survived and had longer and healthier lives. We report a 24-year course of treatment in a patient who was diagnosed with ADA deficiency at 4 months of age. The patient was treated with PEG-ADA, which was the only therapy available for him. The patient's plasma ADA level was regularly monitored and the PEG-ADA dose adjusted accordingly. This treatment has resulted in near-normalization of lymphocyte counts, and his clinical course has been associated with only minor to moderate infections. Thus far, he has had no manifestations of autoimmune or lymphoproliferative disorders. This patient is among the longest to be maintained on PEG-ADA enzyme replacement therapy., (Copyright © 2016 by the American Academy of Pediatrics.)
- Published
- 2016
- Full Text
- View/download PDF
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