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1.
  • Tesi, B., et al. (author)
  • Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis
  • 2015
  • In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 7:1
  • Journal article (peer-reviewed)abstract
    • Background: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. Methods: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. Results: Analyses revealed a mutation detection sensitivity of 97.3 %, an average coverage per gene of 98.0 %, and adequate coverage over 98.6 % of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38 %). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. Conclusions: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.
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2.
  • Yeoh, SA, et al. (author)
  • FACTORS ASSOCIATED WITH SEVERE COVID-19 OUTCOMES IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY: RESULTS FROM THE COVID-19 GLOBAL RHEUMATOLOGY ALLIANCE PHYSICIAN-REPORTED REGISTRY
  • 2022
  • In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 165-166
  • Conference paper (other academic/artistic)abstract
    • There is a paucity of data in the literature about the outcome of patients with idiopathic inflammatory myopathy (IIM) who have been infected with SARS-CoV-2.ObjectivesTo investigate factors associated with severe COVID-19 outcomes in patients with IIM.MethodsData on demographics, number of comorbidities, region, COVID-19 time period, physician-reported disease activity, anti-rheumatic medication exposure at the clinical onset of COVID-19, and COVID-19 outcomes of IIM patients were obtained from the voluntary COVID-19 Global Rheumatology Alliance physician-reported registry of adults with rheumatic disease (from 17 March 2020 to 27 August 2021). An ordinal COVID-19 severity scale was used as primary outcome of interest, with each outcome category being mutually exclusive from the other:a) no hospitalization, b) hospitalization (and no death), or c) death. Odds ratios (OR) were estimated using multivariable ordinal logistic regression. In ordinal logistic regression, the effect size of a categorical predictor can be interpreted as the odds of being one level higher on the ordinal COVID-19 severity scale than the reference category.ResultsComplete hospitalization and death outcome data was available in 348 IIM cases. Mean age was 53 years, and 223 (64.1%) were female. Overall, 167/348 (48.0%) people were not hospitalized, 136/348 (39.1%) were hospitalized (and did not die), and 45/348 (12.9%) died. Older age (OR=1.59 per decade of life, 95%CI 1.32-1.93), male sex (OR=1.63, 95%CI 1.004-2.64; versus female), high disease activity (OR=4.05, 95%CI 1.29-12.76; versus remission), presence of two or more comorbidities (OR=2.39, 95%CI 1.22-4.68; versus none), prednisolone-equivalent dose >7.5 mg/day (OR=2.37, 95%CI 1.27-4.44; versus no glucocorticoid intake), and exposure to rituximab (OR=2.60, 95%CI 1.23-5.47; versus csDMARDs only) were associated with worse COVID-19 outcomes (Table 1).Table 1.Multivariable logistic regression analysis of factors associated with the ordinal COVID-19 severity outcomes. AZA, azathioprine; CI, confidence interval; combo, combination; CSA, ciclosporin; CYC, cyclophosphamide; DMARD, disease-modifying anti-rheumatic drug; b/tsDMARD, biologic/targeted synthetic DMARD, csDMARD, conventional synthetic DMARD; HCQ, hydroxychloroquine; IVIg, intravenous immunoglobulin; LEF, leflunomide; MMF, mycophenolate mofetil; mono, monotherapy; MTX, methotrexate; OR, odds ratio; Ref, reference; RTX, rituximab; SSZ, sulfasalazine; TAC, tacrolimus.VariableOR (95%CI)P-valueVariableOR (95%CI)P-valueAge (per decade)1.59 (1.32-1.93)<0.001ComorbiditiesMale sex1.63 (1.004-2.64)0.048NoneRefNAPrednisolone-equivalent doseOne1.46 (0.79-2.72)0.228NoneRefNATwo or more2.39 (1.22-4.68)0.011>0 to 7.5mg/day1.10 (0.57-2.11)0.779Physician-reported disease activity>7.5mg/day2.37 (1.27-4.44)0.007RemissionRefNAIVIg0.41 (0.15-1.16)0.093Low/moderate1.23 (0.67-2.28)0.504DMARDsHigh4.05 (1.29-12.76)0.018csDMARD only (mono or combi - HCQ, MTX, LEF, SSZ)RefNARegionNo DMARD1.84 (0.90-3.75)0.094EuropeRefNAb/tsDMARD mono or combi (except RTX)1.60 (0.49-5.26)0.435North America0.89 (0.49-1.61)0.694CSA/CYC/TAC mono or combi (except RTX or b/tsDMARDs)1.55 (0.52-4.58)0.429Other4.25 (2.21-8.16)<0.001AZA mono1.70 (0.69-4.19)0.249Time periodMMF mono1.22 (0.53-2.82)0.634Before 15 June 2020RefNAAZA/MMF combi (except RTX or b/tsDMARDs)0.71 (0.25-2.00)0.51716 June - 30 September 20200.58 (0.26-1.27)0.171RTX mono or combi2.60 (1.23-5.47)0.012After 1 October 20200.58 (0.35-0.95)0.032ConclusionThese are the first global registry data on the impact of COVID-19 on IIM patients. Older age, male gender, higher comorbidity burden, higher disease activity, higher glucocorticoid intake and rituximab exposure were associated with worse outcomes. These findings will inform risk stratification and management decisions for IIM patients.ReferencesNoneDisclosure of InterestsSu-Ann Yeoh: None declared, Milena Gianfrancesco: None declared, Saskia Lawson-Tovey: None declared, Kimme Hyrich Speakers bureau: AbbVie unrelated to this work, Grant/research support from: Pfizer, BMS, both unrelated to this work, Anja Strangfeld Speakers bureau: AbbVie, Celltrion, MSD, Janssen, Lilly, Roche, BMS, Pfizer, all unrelated to this work, Laure Gossec Consultant of: AbbVie, Amgen, BMS, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, UCB, all unrelated to this work, Grant/research support from: Amgen, Galapagos, Lilly, Pfizer, Sandoz, all unrelated to this work, Loreto Carmona: None declared, Elsa Mateus Consultant of: Boehringer Ingelheim Portugal, not related to this work, Martin Schaefer: None declared, Christophe Richez Speakers bureau: Abbvie, Amgen, Astra Zeneca, Biogen, BMS, Celltrion, Eli Lilly, Galapagos, GSK, MSD, Novartis, and Pfizer, all unrelated to this abstract, Consultant of: Abbvie, Amgen, Astra Zeneca, Biogen, BMS, Celltrion, Eli Lilly, Galapagos, GSK, MSD, Novartis, and Pfizer, all unrelated to this abstract, Eric Hachulla Speakers bureau: Johnson & Johnson, GlaxoSmithKline, Roche-Chugai, all unrelated to this work, Consultant of: Bayer, Boehringer Ingelheim, GlaxoSmithKline, Johnson & Johnson, Roche-Chugai, Sanofi-Genzyme, all unrelated to this work, Grant/research support from: CSL Behring, GlaxoSmithKline, Johnson & Johnson, Roche-Chugai, Sanofi-Genzyme, all unrelated to this work, Marie Holmqvist: None declared, Carlo Alberto Scirè Grant/research support from: AbbVie, Lilly, both unrelated to this work, Rebecca Hasseli: None declared, Arundathi Jayatilleke: None declared, Tiffany Hsu: None declared, Kristin D’Silva: None declared, Victor Pimentel-Quiroz: None declared, Monica Vasquez del Mercado: None declared, Samuel Katsuyuki Shinjo: None declared, Edgard Reis Neto: None declared, Laurindo Rocha Jr: None declared, Ana Carolina de Oliveira e Silva Montandon Speakers bureau: GSK, not related to this work, Paula Jordan: None declared, Emily Sirotich: None declared, Jonathan Hausmann Speakers bureau: Novartis, Biogen, Pfizer, not related to this work, Consultant of: Novartis, Biogen, Pfizer, not related to this work, Jean Liew Grant/research support from: Pfizer research grant, completed in 2021, not related to this work, Lindsay Jacobsohn: None declared, Monique Gore-Massy Speakers bureau: Aurinia Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, not related to this work, Consultant of: Aurinia Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, not related to this work, Paul Sufka: None declared, Rebecca Grainger Speakers bureau: AbbVie, Janssen, Novartis, Pfizer and Cornerstones, all unrelated to this work, Consultant of: AbbVie, Novartis, both unrelated to this work, Suleman Bhana Shareholder of: Pfizer, Inc, Speakers bureau: AbbVie, Horizon, Novartis, and Pfizer, all unrelated to this work, Consultant of: AbbVie, Horizon, Novartis, and Pfizer, all unrelated to this work, Employee of: Pfizer, Inc, Zachary Wallace: None declared, Philip Robinson Speakers bureau: Abbvie, Janssen, Roche, GSK, Novartis, Lilly, UCB, all unrelated to this work, Paid instructor for: Lilly, unrelated to this work, Consultant of: GSK, Kukdong, Atom Biosciences, UCB, all unrelated to this work, Grant/research support from: Janssen, Pfizer, UCB and Novartis, all unrelated to this work, Jinoos Yazdany Consultant of: Aurinia, Astra Zeneca, Pfizer, all unrelated to this work, Grant/research support from: Astra Zeneca, Gilead, BMS Foundation, all unrelated to this work, Pedro Machado Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this work., Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this work.
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3.
  • Lindqvist Appell, Malin, et al. (author)
  • Nomenclature for alleles of the thiopurine methyltransferase gene
  • 2013
  • In: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:4, s. 242-248
  • Research review (peer-reviewed)abstract
    • The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (Gandgt;A) from TPMT*24 to TPMT*30 and position 611 (Tandgt;C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. Pharmacogenetics and Genomics 23: 242-248
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4.
  • Suiter, Chase C., et al. (author)
  • Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity
  • 2020
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:10, s. 5394-5401
  • Journal article (peer-reviewed)abstract
    • As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
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5.
  • Yeoh, S. E., et al. (author)
  • Relationship between duration of heart failure, patient characteristics, outcomes, and effect of therapy in PARADIGM-HF
  • 2020
  • In: Esc Heart Failure. - : Wiley. - 2055-5822.
  • Journal article (peer-reviewed)abstract
    • Aims Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM-HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM-HF. Methods and results HF duration was categorized as 0-1, >1-2, >2-5, and >5 years. Outcomes were adjusted for prognostic variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP). The primary endpoint was the composite of HF hospitalization or cardiovascular death. The number of patients in each group was as follows: 0-1 year, 2523 (30%); >1-2 years, 1178 (14%); >2-5 years, 2054 (24.5%); and >5 years, 2644 (31.5%). Patients with longer-duration HF were older, more often male, and had worse New York Heart Association class and quality of life, more co-morbidity, and higher troponin-T but similar NT-proBNP levels. The primary outcome rate (per 100 person-years) increased with HF duration: 0-1 year, 8.4 [95% confidence interval (CI) 7.6-9.2]; >1-2 years, 11.2 (10.0-12.7); >2-5 years, 13.4 (12.4-14.6); and >5 years, 14.2 (13.2-15.2);P < 0.001. The hazard ratio was 1.26 (95% CI 1.07-1.48), 1.52 (1.33-1.74), and 1.53 (1.33-1.75), respectively, for >1-2, >2-5, and >5 years, compared with 0-1 year. The benefit of sacubitril/valsartan was consistent across HF duration for all outcomes, with the primary endpoint hazard ratio 0.80 (95% CI 0.67-0.97) for 0-1 year and 0.73 (0.63-0.84) in the >5 year group. For the primary outcome, the number needed to treat for >5 years was 18, compared with 29 for 0-1 year. Conclusions Patients with longer-duration HF had more co-morbidity, worse quality of life, and higher rates of HF hospitalization and death. The benefit of a neprilysin inhibitor was consistent, irrespective of HF duration. Switching to sacubitril/valsartan had substantial benefits, even in patients with long-standing HF.
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6.
  • Yeoh, SA, et al. (author)
  • Factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy: results from the COVID-19 Global Rheumatology Alliance physician-reported registry
  • 2022
  • In: RMD open. - : BMJ. - 2056-5933. ; 8:2
  • Journal article (peer-reviewed)abstract
    • To investigate factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy (IIM).MethodsDemographic data, clinical characteristics and COVID-19 outcome severity of adults with IIM were obtained from the COVID-19 Global Rheumatology Alliance physician-reported registry. A 3-point ordinal COVID-19 severity scale was defined: (1) no hospitalisation, (2) hospitalisation (and no death) and (3) death. ORs were estimated using multivariable ordinal logistic regression. Sensitivity analyses were performed using a 4-point ordinal scale: (1) no hospitalisation, (2) hospitalisation with no oxygen (and no death), (3) hospitalisation with oxygen/ventilation (and no death) and 4) death.ResultsOf 348 patients, 48% were not hospitalised, 39% were hospitalised (and did not die) and 13% died. Older age (OR=1.59/decade, 95% CI 1.31 to 1.91), high disease activity (OR=3.50, 95% CI 1.25 to 9.83; vs remission), ≥2 comorbidities (OR=2.63, 95% CI 1.39 to 4.98; vs none), prednisolone-equivalent dose >7.5 mg/day (OR=2.40, 95% CI 1.09 to 5.28; vs no intake) and exposure to rituximab (OR=2.71, 95% CI 1.28 to 5.72; vs conventional synthetic disease-modifying antirheumatic drugs only) were independently associated with severe COVID-19. In addition to these variables, in the sensitivity analyses, male sex (OR range: 1.65–1.83; vs female) was also significantly associated with severe outcomes, while COVID-19 diagnosis after 1 October 2020 (OR range: 0.51–0.59; vs on/before 15 June 2020) was significantly associated with less severe outcomes, but these associations were not significant in the main model (OR=1.57, 95% CI 0.95 to 2.59; and OR=0.61, 95% CI 0.37 to 1.00; respectively).ConclusionsThis is the first large registry data on outcomes of COVID-19 in people with IIM. Older age, male sex, higher comorbidity burden, high disease activity, prednisolone-equivalent dose >7.5 mg/day and rituximab exposure were associated with severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with IIM.
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7.
  • Atun, Rifat, et al. (author)
  • Sustainable care for children with cancer : a Lancet Oncology Commission
  • 2020
  • In: The Lancet Oncology. - 1470-2045. ; 21:4, s. 185-224
  • Research review (peer-reviewed)abstract
    • We estimate that there will be 13·7 million new cases of childhood cancer globally between 2020 and 2050. At current levels of health system performance (including access and referral), 6·1 million (44·9%) of these children will be undiagnosed. Between 2020 and 2050, 11·1 million children will die from cancer if no additional investments are made to improve access to health-care services or childhood cancer treatment. Of this total, 9·3 million children (84·1%) will be in low-income and lower-middle-income countries. This burden could be vastly reduced with new funding to scale up cost-effective interventions. Simultaneous comprehensive scale-up of interventions could avert 6·2 million deaths in children with cancer in this period, more than half (56·1%) of the total number of deaths otherwise projected. Taking excess mortality risk into consideration, this reduction in the number of deaths is projected to produce a gain of 318 million life-years. In addition, the global lifetime productivity gains of US$2580 billion in 2020–50 would be four times greater than the cumulative treatment costs of $594 billion, producing a net benefit of $1986 billion on the global investment: a net return of $3 for every $1 invested. In sum, the burden of childhood cancer, which has been grossly underestimated in the past, can be effectively diminished to realise massive health and economic benefits and to avert millions of needless deaths.
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