21. Dexamethasone in hospitalized patients with Covid-19Peter Horby, Wei Shen Lim, Martin J. Landray, 2021, original scientific article Abstract: Background: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. Results: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). Conclusions: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).
Keywords: Covid-19 -- drug therapy, dexamethasone
Published in DiRROS: 30.05.2022; Views: 506; Downloads: 332
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22. Neutralizing anti-interferon-[gamma] autoantibodies: an ameliorating factor in COVID-19 infection?Mark Kačar, Paulina Cortes-Acevedo, Vinesh Patel, Clive Carter, Pamela Hughes, Hugh P. McGann, Effrossyni Gkrania-Klotsas, Helen Baxendale, Gabriela Barcenas-Morales, Rainer Doffinger, Sinisa Savic, 2021, short scientific article Keywords: SARS-CoV-2, COVID-19, interferon-gamma, respiratory distress syndrome, nontuberculous mycobacteria, macrophage activation syndrome, acute respiratory distress syndrome
Published in DiRROS: 09.11.2021; Views: 1044; Downloads: 260
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24. Hereditary systemic autoinflammatory diseases and Schnitzler's syndromeMark Kačar, Shelly Pathak, Sinisa Savic, 2019, review article Abstract: The systemic autoinflammatory diseases are disorders of the innate immune system distinguished by severe inflammation resulting from dysregulation of the innate immune system. Hereditary fever syndromes, such as FMF, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes and mevalonate kinase deficiency, were the first group of systemic autoinflammatory diseases for which a genetic basis was established, between 1999 and 2001. Currently according to the latest report of the international union of immunological societies, 37 separate monogenic disorders were classified as autoinflammatory. In addition to the abovementioned monogenic conditions, we describe Schnitzler's syndrome, a well-defined, acquired autoinflammatory condition without a clear genetic basis. For the purposes of this review, we discuss several conditions defined by the latest consensus process as systemic autoinflammatory diseases. We focus on those disorders where recent studies have contributed to further phenotypic characterization or had an impact on clinical management.
Keywords: pyrin, Schnitzler syndrome, haploinsufficiency, autoinflammatory diseases, pyrin-associated autoinflammatory diseases, NLRP3-related autoinflammatory diseases, undifferentiated systemic autoinflammatory disease, relopathies
Published in DiRROS: 08.04.2021; Views: 1261; Downloads: 963
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25. The efficacy, safety and tolerability of canakinumab in the treatment of familial Mediterranean fever : a systematic review of the literatureMark Kačar, Sinisa Savic, Jeroen CH van der Hilst, 2020, review article Abstract: Familial Mediterranean Fever (FMF) is the most prevalent genetic autoinflammatory disorder. In most patients, treatment with colchicine can prevent attacks of fever and inflammation. However, 5%-10% of patients are resistant to colchicine treatment, while a similar percentage cannot tolerate colchicine in doses needed to prevent attacks. For these patients, Canakinumab, a full human antibody against IL-1[beta], has been approved recently by the FDA and EMA. In this article, we present a systematic review of the long-term efficacy, safety, and tolerability of Canakinumab in FMF patients who cannot tolerate colchicine or who are resistant to colchicine treatment.
Keywords: familial Mediterranean fever -- therapy -- review, monoclonal antibodies, canakinumab, anti-IL1 therapy
Published in DiRROS: 08.04.2021; Views: 1314; Downloads: 767
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26. Mixed results with baricitinib in biological-resistant adult-onset Still's disease and undifferentiated systemic autoinflammatory diseaseMark Kačar, John Fitton, Andrew K Gough, Maya H Buch, Dennis McGonagle, Sinisa Savic, 2020, original scientific article Abstract: This clinical case series describes our experience with the use of Janus kinase 1/2 inhibitor baricitinib in two patients suffering from refractory adult-onset Still's disease (AOSD) as well as in one case suffering from AOSD-like autoinflammatory disease in the context of myelodysplastic syndrome. All patients suffered from disease nonresponsive to conventional Disease-modifying antirheumatic drugs (DMARDs) as well as biological therapies including interleukin (IL)-1 and IL-6 blockade, relying instead on high daily doses of prednisolone. We also report the first case of Pneumocystis jirovecii infection following baricitinib use.
Keywords: adult onset Still's disease -- drug therapy, ankylosing spondylitis, arthritis, antirheumatic agents, undifferentiated systemic autoinflammatory disease, disease-modifying antirheumatic drugs
Published in DiRROS: 08.04.2021; Views: 1328; Downloads: 850
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27. Evidence of B cell clonality and investigation into properties of the IgM in patients with Schnitzler syndromeShelly Pathak, Dorota Rowczenio, Samuel Lara-Reyna, Mark Kačar, Roger Owen, Gina Doody, Karoline Krause, Helen J Lachmann, Rainer Doffinger, Darren Newton, Sinisa Savic, 2020, original scientific article Abstract: The Schnitzler Syndrome (SchS) is an acquired, autoinflammatory condition successfully treated with IL-1 inhibition. The two main defining features of this late-onset condition are neutrophilic urticarial dermatoses (NUD) and the presence of an IgM monoclonal component. While the former aspect has been extensively studied in this disease setting, the enigmatic paraproteinaemia and its potential consequential effects within SchS, has not previously been thoroughly addressed. Previous studies analyzing clonal B cell repertoires have largely focused on autoimmune disorders such as Systemic Lupus Erythematous (SLE) and hematological malignancies such as Chronic Lymphocytic Leukaemia (CLL), where B-cell clonality is central to disease pathology. The present study uses next-generation sequencing to provide detailed insight into aspects of B cell VDJ recombination and properties of the resulting immunoglobulin chains. An overview of IgH regional dynamics in 10 SchS patients, with a particular focus on CDR3 sequences and VDJ gene usage is reported, highlighting the presence of specific B cell expansions. Protein microarray detected a substantial proportion of autoreactive IgM to nuclear target proteins, though a single universal target was not identified. Together, these genetic and functional findings impart new understanding into this rare disorder.
Keywords: Schnitzler syndrome, B-lymhocytes, paraproteinemias, pararoteins, immunoglobulin M, autoinflammatory diseases, IgM
Published in DiRROS: 08.04.2021; Views: 1214; Downloads: 820
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28. Identification of critical transcriptomic signaling pathways in patients with H syndrome and Rosai-Dorfman diseaseSamuel Lara-Reyna, James A. Poulter, Elton J.R. Vasconcelos, Mark Kačar, Michael F. McDermott, Reuben Tooze, Rainer Doffinger, Sinisa Savic, 2021, original scientific article Abstract: Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68+, S100+, and CD1a[minus] histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFN[gamma] were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms "type I IFN," "IFN[gamma] signaling pathway," and "immune responses" as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFN[gamma] signature. These findings may help find better therapeutic options for this rare disorder.
Keywords: interferon-gamma, H syndrome, systemic autoinflammatory disease
Published in DiRROS: 08.04.2021; Views: 1131; Downloads: 584
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29. Somatic mutations and the risk of undifferentiated autoinflammatory disease in MDS : an under-recognized but prognostically important complicationAbdulla Watad, Mark Kačar, Nicola Luigi Bragazzi, Qiao Zhou, Miriam Jassam, Jan Taylor, Eve Roman, Alexandra Smith, Richard A. Jones, Howard Amital, 2021, original scientific article Abstract: Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS. Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somaticmutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated "autoinflammatory disease" (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups. Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p < 0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02-4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22-6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080). Conclusions: Autoinflammatory complications are common inMDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis.
Keywords: myelodysplastic syndromes - genetics, autoinflammation, undifferentiated autoinflammatory disease, molecular characterization, somatic mutations
Published in DiRROS: 31.03.2021; Views: 1175; Downloads: 798
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30. Cultural ecosystem services provided by the biodiversity of forest soils : a European reviewJurga Motiejunaite, Isabella Børja, Ivika Ostonen, Mark Bakker, Brynhildur Bjarnadottir, Ivano Brunner, Reda Iršenaite, Tanja Mrak, Edda Oddsdottir, Tarja Lehto, 2019, original scientific article Abstract: Soil is one of the most species-rich habitats and plays a crucial role in the functioning of terrestrial ecosystems. It is acknowledged that soils and their biota deliver many ecosystem services. However, up to now, cultural ecosystem services (CES) provided by soil biodiversity remained virtually unknown. Here we present a multilingual and multisubject literature review on cultural benefits provided by belowground biota in European forests. We found 226 papers mentioning impact of soil biota on the cultural aspects of human life. According to the reviewed literature, soil organisms contribute to all CES. Impact on CES, as reflected in literature, was highest for fungi and lowest for microorganisms and mesofauna. Cultural benefits provided by soil biota clearly prevailed in the total of the reviewed references, but there were also negative effects mentioned in six CES. The same organism groups or even individual species may have negative impacts within one CES and at the same time act as an ecosystem service provider for another CES. The CES were found to be supported at several levels of ecosystem service provision: from single species to two or more functional/taxonomical groups and in some cases morphological diversity acted as a surrogate for species diversity. Impact of soil biota on CES may be both direct % by providing the benefits (or dis-benefits) and indirect through the use of the products or services obtained from these benefits. The CES from soil biota interacted among themselves and with other ES, but more than often, they did not create bundles, because there exist temporal fluctuations in value of CES and a time lag between direct and indirect benefits. Strong regionality was noted for most of CES underpinned by soil biota: the same organism group or species may have strong impact on CES (positive, negative or both) in some regions while no, minor or opposite effects in others. Contrarily to the CES based on landscapes, in the CES provided by soil biota distance between the ecosystem and its CES benefiting area is shorter (CES based on landscapes are used less by local people and more by visitors, meanwhile CES based on species or organism groups are used mainly by local people). Our review revealed the existence of a considerable amount of spatially fragmented and semantically rich information highlighting cultural values provided by forest soil biota in Europe.
Keywords: soil biota, forests, soil ecosystem services, Europe
Published in DiRROS: 20.02.2020; Views: 1794; Downloads: 1021
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