| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 3. |
- Jimenez, J. L., et al.
(författare)
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Evolution of Organic Aerosols in the Atmosphere
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 326:5959, s. 1525-1529
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Tidskriftsartikel (refereegranskat)abstract
- Organic aerosol (OA) particles affect climate forcing and human health, but their sources and evolution remain poorly characterized. We present a unifying model framework describing the atmospheric evolution of OA that is constrained by high-time-resolution measurements of its composition, volatility, and oxidation state. OA and OA precursor gases evolve by becoming increasingly oxidized, less volatile, and more hygroscopic, leading to the formation of oxygenated organic aerosol (OOA), with concentrations comparable to those of sulfate aerosol throughout the Northern Hemisphere. Our model framework captures the dynamic aging behavior observed in both the atmosphere and laboratory: It can serve as a basis for improving parameterizations in regional and global models.
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| 4. |
- Mehra, A., et al.
(författare)
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The persistence of a proxy for cooking emissions in megacities: a kinetic study of the ozonolysis of self-assembled films by simultaneous small and wide angle X-ray scattering (SAXS/WAXS) and Raman microscopy
- 2021
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Ingår i: Faraday Discussions. - 1359-6640. ; 226, s. 382-408
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Tidskriftsartikel (refereegranskat)abstract
- Cooking emissions account for a significant proportion of the organic aerosols emitted into the urban environment and high pollution events have been linked to an increased organic content on urban particulate matter surfaces. We present a kinetic study on surface coatings of self-assembled (semi-solid) oleic acid-sodium oleate cooking aerosol proxies undergoing ozonolysis. We found clear film thickness-dependent kinetic behaviour and measured the effect of the organic phase on the kinetics for this system. In addition to the thickness-dependent kinetics, we show that significant fractions of unreacted proxy remain after extensive ozone exposure and that this effect scales approximately linearly with film thickness, suggesting that a late-stage inert reaction product may form and inhibit reaction progress - effectively building up an inert crust. We determine this by using a range of simultaneous analytical techniques; most notably Small-Angle X-ray Scattering (SAXS) has been used for the first time to measure the reaction kinetics of films of a wide range of thicknesses from ca. 0.59 to 73 mu m with films <10 mu m thick being of potential atmospheric relevance. These observations have implications for the evolution of particulate matter in the urban environment, potentially extending the atmospheric lifetimes of harmful aerosol components and affecting the local urban air quality and climate.
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| 5. |
- Mehra, A., et al.
(författare)
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Using highly time-resolved online mass spectrometry to examine biogenic and anthropogenic contributions to organic aerosol in Beijing
- 2021
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Ingår i: Faraday Discussions. - 1359-6640. ; 226, s. 382-408
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Tidskriftsartikel (refereegranskat)abstract
- Organic aerosols, a major constituent of fine particulate mass in megacities, can be directly emitted or formed from secondary processing of biogenic and anthropogenic volatile organic compound emissions. The complexity of volatile organic compound emission sources, speciation and oxidation pathways leads to uncertainties in the key sources and chemistry leading to formation of organic aerosol in urban areas. Historically, online measurements of organic aerosol composition have been unable to resolve specific markers of volatile organic compound oxidation, while offline analysis of markers focus on a small proportion of organic aerosol and lack the time resolution to carry out detailed statistical analysis required to study the dynamic changes in aerosol sources and chemistry. Here we use data collected as part of the joint UK-China Air Pollution and Human Health (APHH-Beijing) collaboration during a field campaign in urban Beijing in the summer of 2017 alongside laboratory measurements of secondary organic aerosol from oxidation of key aromatic precursors (1,3,5-trimethyl benzene, 1,2,4-trimethyl benzene, propyl benzene, isopropyl benzene and 1-methyl naphthalene) to study the anthropogenic and biogenic contributions to organic aerosol. For the first time in Beijing, this study applies positive matrix factorisation to online measurements of organic aerosol composition from a time-of-flight iodide chemical ionisation mass spectrometer fitted with a filter inlet for gases and aerosols (FIGAERO-ToF-I-CIMS). This approach identifies the real-time variations in sources and oxidation processes influencing aerosol composition at a near-molecular level. We identify eight factors with distinct temporal variability, highlighting episodic differences in OA composition attributed to regional influences and in situ formation. These have average carbon numbers ranging from C-5-C-9 and can be associated with oxidation of anthropogenic aromatic hydrocarbons alongside biogenic emissions of isoprene, alpha -pinene and sesquiterpenes.
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| 6. |
- Chavatza, K, et al.
(författare)
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EULAR RECOMMENDATION-BASED QUALITY INDICATORS (QIS) FOR SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): ELABORATION, FINAL SET, PERFORMANCE AND INITIAL VALIDATION
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 635-636
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Targets of therapy and quality of care are receiving increased attention in systemic lupus erythematosus (SLE).Objectives:To develop Quality Indicators (QIs) for the care of SLE patients based on the EULAR recommendations, and assess their performance.Methods:Using the published EULAR recommendations for SLE, we developed 44 candidate QIs. These were independently rated for validity and feasibility by 12 experts, analysed by a modified RAND/UCLA model and further scrutinized based on the scorings and expert opinion. (Fig.1) Adherence to the final set of QIs was tested in a cohort of 220 SLE patients combined with an assessment on its impact on disease outcomes such as flares, hospitalizations and organ damage.Results:The panel rated 18 QIs as valid and feasible. These involve diagnosis; disease and damage assessment; monitoring for lupus nephritis and drug toxicity; therapy and targets of therapy; fertility and pregnancy; and adjunct therapy (preventive measures for osteoporosis, vaccination, cardiovascular disease). On average, SLE patients received 54% (95%CI 52–56%) of the indicated care with adherence ranging from 41% for QIs related to monitoring to 88% for treatment-related QIs. Regarding targets of therapy, sustained remission or low disease activity were achieved in 27%, while 94% of patients received low-dose glucocorticoids, and 92% the recommended hydroxychloroquine dose. Dependent upon individual QI tested, adherence for lupus nephritis-related QIs was 88% for receiving appropriate adjunct therapy (ACE inhibitors) to 100% for being treated with the indicated immunosuppressive treatment. In contrast, adherence to QIs related to preventive measures and other adjunct therapies was moderate to low. Notably, patients who were eligible for cardiovascular risk modification, vaccination, and osteoporosis management received lower quality of care (40.5%, 47.7% and 45.5% respectively) while 91.4% had sunscreen protection. In reference to laboratory work-up and monitoring, complete laboratory work-up at diagnosis was performed in 48%, while disease activity and damage, were fully assessed only in 14.1% (in three consecutive visits) and 28.6% (annually) respectively, Similarly, reproductive health and pregnancy counselling adherence rates were modest estimated at 50% and 62% respectively. Higher adherence to the indicated care during follow-up (monitoring QIs) was associated with reduced risk for adverse outcomes during the last year of observation (OR 0.97, 95%CI 0.96-0.99). Patients who achieved sustained remission or LLDAS, exhibited fewer flares (OR=0.15, p-value<0.001) and damage accrual (OR=0.35, p-value<0.001). Of interest, patients who received low-dose of GCs or were appropriately vaccinated, had a lower risk of experiencing a flare (OR=0.23 and 0.46 respectively).Conclusion:A set of 18 QIs based on the EULAR recommendations for SLE was developed to be used towards improving care in SLE. Initial real-life data suggest variable degree of adherence with higher adherence resulting in reduced adverse outcomes.References:[1]Fanouriakis, et al., 2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus. In Annals of the Rheumatic Diseases (Vol. 78, Issue 6, pp. 736–745). BMJ Publishing Group. https://doi.org/10.1136/annrheumdis-2019-215089.[2]Nikolopoulos, D., et al., Evolving phenotype of systemic lupus erythematosus in Caucasians: low incidence of lupus nephritis, high burden of neuropsychiatric disease and increased rates of late-onset lupus in the ‘Attikon’ cohort. Lupus, 29(5), 514–522. https://doi.org/10.1177/0961203320908932.Acknowledgements:This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390)Disclosure of Interests:None declared
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| 7. |
- Jones, RB, et al.
(författare)
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Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:3, s. 399-405
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Tidskriftsartikel (refereegranskat)abstract
- Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV.MethodsWe conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study.ResultsAt baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI −7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3).ConclusionMMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate.Trial registration numberNCT00414128.
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| 8. |
- Reed, Mark S., et al.
(författare)
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The future of the uplands
- 2009
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Ingår i: Land use policy. - : Elsevier Limited. - 0264-8377 .- 1873-5754. ; 26:Supplement 1
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Tidskriftsartikel (refereegranskat)abstract
- Upland areas provide UK society with many important functions, goods and services, but have experienced a number of disturbing trends and face an uncertain future. This paper outlines historic, current and future drivers of environmental, economic, socio-cultural and policy change in UK uplands, and assesses how these have affected or are likely to affect ways in which land is used and the provision of ecosystem services. Information is synthesised into scenarios summarising a range of possible futures anticipated for UK uplands to 2060 and beyond. Finally, innovations in science, technology, governance and policy are evaluated that could enable uplands to continue providing key ecosystem services under a range of scenarios. The paper concludes that many upland areas will need to be prepared for significant reductions in grazing and prescribed burning. Conversely, other areas could experience agricultural intensification, for example significant increases in grazing or an expansion of arable or bioenergy crops into upland valleys, due to anticipated increases in global demand for food and energy. These scenarios will take place in the context of climate change. Many may take place together and may interact with each other, with complex and unpredictable implications for the upland environment, economy and society. In this context, a number of advances are needed in science, technology and policy to maintain viable uplandcommunities and the future provision of ecosystem services. These may include funding for ecological and hydrological restoration via carbon offsetting or other means. It may also involve advances in ecosystem service modelling, mapping and valuation, which through stakeholder participation could facilitate more integrated rural planning. New forms of environmental governance need to be explored that can empower those interested in developing upland economies to maintain thriving upland communities, while managing the ecosystem services they provide as efficiently as possible.
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| 9. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 10. |
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| 11. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19
- 2020
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Ingår i: Postdigital Science and Education. - : Springer Science and Business Media LLC. - 2524-4868 .- 2524-485X. ; 2:3, s. 1069-1230
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A collection of 84 author's testimonies and workspace photographs between 18 March and 5 May 2020.
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| 12. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19 : The New Normal
- 2022
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Ingår i: Postdigital Science and Education. - : Springer Science and Business Media LLC. - 2524-485X .- 2524-4868. ; 4:3, s. 877-1015
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Tidskriftsartikel (refereegranskat)abstract
- On 17 March 2020, Postdigital Science and Education launched a call for testimonies about teaching and learning during very frst Covid-19 lockdowns. The resulting article, ‘Teaching in the Age of Covid-19’ (attached), presents 81 written testimonies and 80 workspace photographs submitted by 84 authors from 19 countries. On 17 March 2021, Postdigital Science and Education launched a call for a sequel article of testimonies about teaching and learning during very first Covid-19 lockdowns. The resulting article, ‘Teaching in the Age of Covid-19—1 Year Later’(attached), consists of 74 textual testimonies and 76 workspace photographs submitted by 77 authors from 20 countries.These two articles have been downloaded almost 100,000 times and have been cited more than 100 times. This shows their value as historical documents. Recent analyses, such as ‘Teaching in the Age of Covid-19—A Longitudinal Study ’(attached), also indicate their strong potential for educational research. As the Covid-19 pandemic seems to wind down, pandemic experiences have entered the mainstream. They shape all educational research of today and arguably do not require special treatment. Yet, our unique series of pandemic testimonies provides a unique opportunity to longitudinally trace what happens to the same people over the years—and this opportunity should not be missed.Today, we launch a call for fnal sequel: Teaching in the Age of Covid-19—The New Normal. In this sequel, we would like to hear about ways in which you—contributors to the previous articles—have established your own new normal. We hope that this will be the last iteration in this series of testimony articles. Unless the world faces another strong pandemic outburst, we would like to end the series with this last article.
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| 13. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19—1 Year Later
- 2021
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Ingår i: Postdigital Science and Education. - : Springer. - 2524-485X .- 2524-4868. ; 3:3, s. 1073-1223
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Tidskriftsartikel (refereegranskat)
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| 14. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 15. |
- Law, PJ, et al.
(författare)
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Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8, s. 14175-
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Tidskriftsartikel (refereegranskat)abstract
- Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
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| 16. |
- Lyons, PA, et al.
(författare)
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Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 5120-
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
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| 17. |
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| 18. |
- van Vollenhoven, R, et al.
(författare)
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A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS)
- 2017
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 76:3, s. 554-561
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Tidskriftsartikel (refereegranskat)abstract
- Treat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.MethodsAn international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.ResultsThe task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.ConclusionsThe work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.
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| 19. |
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| 20. |
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| 21. |
- Alchi, B, et al.
(författare)
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Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: data from the European Group for Blood and Marrow Transplantation registry
- 2013
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Ingår i: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 22:3, s. 245-253
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Tidskriftsartikel (refereegranskat)abstract
- Patients with systemic lupus erythematosus (SLE) refractory to conventional immunosuppression suffer substantial morbidity and mortality due to active disease and treatment toxicity. Immunoablation followed by autologous stem cell transplantation (ASCT) is a novel therapeutic strategy that potentially offers new hope to these patients. Methods This retrospective survey reviews the efficacy and safety of ASCT in 28 SLE patients from eight centres reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 2001 and 2008. Results Median disease duration before ASCT was 52 (nine to 396) months, 25/28 SLE patients (89%) were female, age 29 (16–48) years. At the time of ASCT, eight (one to 11) American College of Rheumatology (ACR) diagnostic criteria for SLE were present and 17 (60%) patients had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte-colony stimulating factor in 93% of patients, and ex vivo CD34 stem cell selection was performed in 36%. Conditioning regimens were employed with either low ( n = 10) or intermediate (18) intensities. With a median follow-up of 38 (one to 110) months after ASCT, the five-year overall survival was 81 ± 8%, disease-free survival was 29 ± 9%, relapse incidence (RI) was 56 ± 11% and non-relapse mortality was 15 ± 7%. Graft manipulation by CD34+ selection was associated with a lower RI ( p = 0.001) on univariate analysis. There were five deaths within two years after ASCT: three caused by infection, one by secondary autoimmune disease and one by progressive SLE. Conclusions Our data further support the concept of immunoablation and ASCT to re-induce long-term clinical and serologic remissions in refractory SLE patients even in the absence of maintenance therapy. This study also suggests a beneficial effect of ex vivo graft manipulation on prevention of relapses post-transplantation in SLE.
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| 22. |
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| 23. |
- Bannan, T. J., et al.
(författare)
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A method for extracting calibrated volatility information from the FIGAERO-HR-ToF-CIMS and its experimental application
- 2019
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Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 12:3, s. 1429-1439
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Tidskriftsartikel (refereegranskat)abstract
- The Filter Inlet for Gases and AEROsols (FIGAERO) is an inlet specifically designed to be coupled with the Aerodyne High-Resolution Time-of-Flight Chemical Ionization Mass Spectrometer (HR-ToF-CIMS). The FIGAERO-HR-ToF-CIMS provides simultaneous molecular information relating to both the gas- and particle-phase samples and has been used to extract vapour pressures (VPs) of the compounds desorbing from the filter whilst giving quantitative concentrations in the particle phase. However, such extraction of vapour pressures of the measured particle-phase components requires use of appropriate, well-defined, reference compounds. Vapour pressures for the homologous series of polyethylene glycols (PEG) ((H-(O-CH 2 CH 2 ) n -OH) for n = 3 to n = 8), covering a range of vapour pressures (VP) (10 -1 to 10 -7 Pa) that are atmospherically relevant, have been shown to be reproduced well by a range of different techniques, including Knudsen Effusion Mass Spectrometry (KEMS). This is the first homologous series of compounds for which a number of vapour pressure measurement techniques have been found to be in agreement, indicating the utility as a calibration standard, providing an ideal set of benchmark compounds for accurate characterization of the FIGAERO for extracting vapour pressure of measured compounds in chambers and the real atmosphere. To demonstrate this, single-component and mixture vapour pressure measurements are made using two FIGAERO-HR-ToF-CIMS instruments based on a new calibration determined from the PEG series. VP values extracted from both instruments agree well with those measured by KEMS and reported values from literature, validating this approach for extracting VP data from the FIGAERO. This method is then applied to chamber measurements, and the vapour pressures of known products are estimated. © 2019 Author(s).
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| 24. |
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| 25. |
- Chavatza, K, et al.
(författare)
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Quality indicators for systemic lupus erythematosus based on the 2019 EULAR recommendations: development and initial validation in a cohort of 220 patients
- 2021
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 80:9, s. 1175-1182
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Tidskriftsartikel (refereegranskat)abstract
- Quality of care is receiving increased attention in systemic lupus erythematosus (SLE). We developed quality indicators (QIs) for SLE based on the 2019 update of European League Against Rheumatism recommendations.MethodsA total of 44 candidate QIs corresponding to diagnosis, monitoring and treatment, were independently rated for validity and feasibility by 12 experts and analysed by a modified Research and Development Corporation/University of California Los Angeles model. Adherence to the final set of QIs and correlation with disease outcomes (flares, hospitalisations and organ damage) was tested in a cohort of 220 SLE patients with a median monitoring of 2 years (IQR 2–4).ResultsThe panel selected a total of 18 QIs as valid and feasible. On average, SLE patients received 54% (95% CI 52.3% to 56.2%) of recommended care, with adherence ranging from 44.7% (95% CI 40.8% to 48.6%) for diagnosis-related QIs to 84.3% (95% CI 80.6% to 87.5%) for treatment-related QIs. Sustained remission or low disease activity were achieved in 26.8% (95% CI 21.1% to 33.2%). Tapering of prednisone dose to less than 7.5 mg/day was achieved in 93.6% (95% CI 88.2% to 97.0%) while 73.5% (95% CI 66.6% to 79.6%) received the recommended hydroxychloroquine dose. Higher adherence to monitoring-related QIs was associated with reduced risk for a composite adverse outcome (flare, hospitalisation or damage accrual) during the last year of observation (OR 0.97 per 1% adherence rate, 95% CI 0.96 to 0.99).ConclusionWe developed QIs for assessing and improving the care of SLE patients. Initial real-life data suggest face validity, but a variable degree of adherence and a need for further improvement.
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Lyons, Paul A, et al.
(författare)
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Genetically Distinct Subsets within ANCA-Associated Vasculitis
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 367:3, s. 214-223
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)
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| 30. |
- Moiseev, Sergey, et al.
(författare)
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2020 international consensus on ANCA testing beyond systemic vasculitis
- 2020
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Ingår i: Autoimmunity Reviews. - : Elsevier BV. - 1568-9972. ; 19:9
-
Forskningsöversikt (refereegranskat)abstract
- This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn's disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered.
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| 31. |
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| 32. |
- Mukhtyar, C., et al.
(författare)
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EULAR recommendations for the management of large vessel vasculitis
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 68:3, s. 318-323
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. Methods: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.
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| 33. |
- Mukhtyar, C., et al.
(författare)
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EULAR recommendations for the management of primary small and medium vessel vasculitis
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 68:3, s. 310-317
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group ( consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.
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| 34. |
- Smith, RM, et al.
(författare)
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Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis
- 2020
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 79:9, s. 1243-1249
-
Tidskriftsartikel (refereegranskat)abstract
- Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.
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| 35. |
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| 36. |
- Smith, RM, et al.
(författare)
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Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial
- 2023
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 82:7, s. 937-944
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Tidskriftsartikel (refereegranskat)abstract
- Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.MethodsRITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).ResultsRituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups.ConclusionsFollowing induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.Trial registration numberNCT01697267; ClinicalTrials.gov identifier
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| 37. |
- Stanway, James, et al.
(författare)
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IgA vasculitis nephritis-outcomes in adult-onset disease
- 2024
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Ingår i: Rheumatology. - : OXFORD UNIV PRESS. - 1462-0324 .- 1462-0332.
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle-aged adults (35-64) and elderly patients (>= 64 years) focusing on kidney outcomes. Methods: We identified patients with renal biopsy-confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. Results: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% elderly (>64 years). Median follow-up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle-aged (13.7%) and younger adults (2.9%) (chi(2 )11.6, P = 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and estimated glomerular filtration rate < 30 ml/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. Conclusion: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.
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| 38. |
- Tack, J., et al.
(författare)
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An expert consensus definition of failure of a treatment to provide adequate relief (F-PAR) for chronic constipation - an international Delphi survey
- 2017
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Ingår i: Alimentary Pharmacology & Therapeutics. - : Wiley. - 0269-2813. ; 45:3, s. 434-442
-
Tidskriftsartikel (refereegranskat)abstract
- Background As treatments for constipation become increasingly available, it is important to know when to progress along the treatment algorithm if the patient is not better. To establish the definition of failure of a treatment to provide adequate relief (F-PAR) to support this management and referral process in patients with chronic constipation. We conducted an international Delphi Survey among gastroenterologists and general practitioners with a special interest in chronic constipation. An initial questionnaire based on recognised rating scales was developed following a focus group. Data were collected from two subsequent rounds of questionnaires completed by all authors. Likert scales were used to establish a consensus on a shorter list of more severe symptoms. The initial focus group yielded a first round questionnaire with 84 statements. There was good consensus on symptom severity and a clear severity response curve, allowing 67 of the symptom-severity pairings to be eliminated. Subsequently, a clear consensus was established on further reduction to eight symptom statements in the final definition, condensed by the steering committee into five diagnostic statements (after replicate statements had been removed). We present an international consensus on chronic constipation, of five symptoms and their severities, any of which would be sufficient to provide clinical evidence of treatment failure. We also provide data representing an expert calibration of commonly used rating scales, thus allowing results of clinical trials expressed in terms of those scales to be converted into estimates of rates of provision of adequate relief.
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| 39. |
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| 40. |
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| 41. |
- Bello, Gianluca, et al.
(författare)
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Characterization of the aggregates formed by various bacterial lipopolysaccharides in solution and upon interaction with antimicrobial peptides
- 2015
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 31:2, s. 741-751
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Tidskriftsartikel (refereegranskat)abstract
- The biophysical analysis of the aggregates formed by different chemotypes of bacterial lipopolysaccharides (LPS) before and after challenge by two different anti-endotoxic antimicrobial peptides (LL37 and bovine lactoferricin), was performed in order to determine their effect on the morphology of LPS aggregates. Small-angle neutron scattering (SANS) and cryogenic transmission electron microscopy (cryoTEM) were used to examine the structures formed by both smooth and rough LPS chemotypes and the effect of the peptides, by visualization of the aggregates and analysis of the scattering data by means of both mathematical approximations and defined models. The data showed that the structure of LPS determines the morphology of the aggregates and inuences the binding activity of both peptides. The morphologies of the worm-like micellar aggregates formed by the smooth LPS were relatively unaltered by the presence of the peptides due to their pre-existing high degree of positive curvature being little affected by their association with either peptide. On the other hand the aggregates formed by the rough LPS chemotypes, showed marked morphological changes from lamellar structures to ordered micellar networks, induced by the increase in positive curvature engendered upon association with the peptides. The combined use of cryoTEM and SANS proved to be a very useful tool for studying the aggregation properties of LPS in solution at biologically relevant concentrations.
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| 42. |
- Bertsias, GK, et al.
(författare)
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Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis
- 2012
-
Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 71:11, s. 1771-1782
-
Tidskriftsartikel (refereegranskat)abstract
- To develop recommendations for the management of adult and paediatric lupus nephritis (LN).MethodsThe available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.ResultsImmunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IVA or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.ConclusionsRecommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.
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| 43. |
- Corman, ML, et al.
(författare)
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Consensus conference on the stapled transanal rectal resection (STARR) for disordered defaecation
- 2006
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Ingår i: Colorectal Disease. - : Wiley. - 1462-8910 .- 1463-1318. ; 8:2, s. 98-101
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Tidskriftsartikel (refereegranskat)abstract
- An international working party was convened in Rome, Italy on 16–17 June, 2005, with the purpose of developing a consensus on the application of the circular stapling instrument to the treatment of certain rectal conditions, the so-called Stapled Transanal Rectal Resection (STARR). Since the procedure has been submitted to only limited objective analysis it was felt prudent to hold a meeting of interested individuals for the purpose of evaluating the current status and to make conclusions and recommendations concerning the applicability of this new approach.
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| 44. |
- de Groot, Kirsten, et al.
(författare)
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Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis A Randomized Trial
- 2009
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Ingår i: Annals of Internal Medicine. - 0003-4819. ; 150:10, s. 3-670
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity. Objective: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission. Design: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment. Setting: 42 centers in 12 European countries. Patients: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease. Intervention: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone. Measurement: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes). Results: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]). Limitations: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited. Conclusion: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia. Primary Funding Source: The European Union.
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| 45. |
- Fanouriakis, A, et al.
(författare)
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2019 update of the EULAR recommendations for the management of systemic lupus erythematosus
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:6, s. 736-745
-
Tidskriftsartikel (refereegranskat)abstract
- Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007–12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
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| 46. |
- Fanouriakis, A, et al.
(författare)
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2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis
- 2020
-
Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 79:6, s. 713-723
-
Tidskriftsartikel (refereegranskat)abstract
- To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.ResultsThe changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
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| 47. |
- Fanouriakis, Antonis, et al.
(författare)
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EULAR recommendations for the management of systemic lupus erythematosus : 2023 update
- 2024
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 83:1, s. 15-29
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence.METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item.RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease.CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.
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| 48. |
- Geetha, Duvuru, et al.
(författare)
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Rituximab for treatment of severe renal disease in ANCA associated vasculitis
- 2016
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Ingår i: JN. Journal of Nephrology. - : Springer. - 1121-8428 .- 1724-6059. ; 29:2, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking.MethodsWe conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events.ResultsA total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2 (7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed.ConclusionsThis study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.
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| 49. |
- Glass, Jayne, et al.
(författare)
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Learning from European Rural Movements : Research to inform a Scottish approach
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- To inform the development of a rural movement in Scotland, this report explores the key characteristics, roles and methods of engagement employed by established rural movements in other European countries.We studied rural movements in 10 countries (Albania, England, Estonia, Finland, Ireland, Latvia, Lithuania, the Netherlands, Northern Ireland, Sweden). We collected information via a desk-based review of relevant literature, interviews with representatives from each of the movements, and an online seminar to discuss the initial findings (hosted by the EuropeanRural Communities Alliance).We identified six overarching themes with associated learning points for Scotland. The themes relate to the structure of the organisation, collaboration, purpose, activities, relationship with government, and place-based action.The findings demonstrate how rural movements represent an organised approach to providing a network and voice for rural areas, their people and those working to support rural development. An important role for the movements is advocacy to shape local, regional and national policy, while another important role is enabling shared learning and knowledge exchange. The character of each movement reflects and responds to the national context in which it operates, including the system of administration and culture.Three insights can be put forward from this research to inform the Scottish approach. We suggest that these are used as a basis for ongoing discussions between Scottish Government, Scottish Rural Action and others seeking to develop an effective and impactful Scottish rural movement:A Scottish rural movement should bring together diverse actors to inform and influence policy.A Scottish rural movement needs a clear identity and clarity of purpose related to networking and knowledge sharing.A Scottish rural movement should be supported to develop constructive relationships with LEADER LAGs and staff to ensure that the movement represents local issues and needs effectively.
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- Göçeroǧlu, Arda, et al.
(författare)
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ANCA-associated glomerulonephritis : Risk factors for renal relapse
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild±moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8±14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.
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