21 research outputs found
Autoantibodies and the type I interferon system in idiopathic inflammatory myopathies
Idiopathic inflammatory myopathies (IIM), also known as myositis, are rare autoimmune diseases, characterized by proximal muscle weakness and inflammatory cells in skeletal muscle tissue. The most common subgroups are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). New subgroups have been recognized, such as immunemediated necrotizing myopathy (IMNM) and the antisynthetase syndrome (ASS). Autoantibodies are common and some of them specific for myositis. The most frequent is the anti-Jo-1 autoantibody, which is associated not only with myositis but also with interstitial lung disease (ILD) and arthritis. The etiology of IIM is still unknown but environmental and genetic factors are believed to contribute to disease susceptibility. Accumulating data indicate a role of the type I interferons (IFNs) in myositis. The treatment of IIM (glucocorticoids and immunomodulatory drugs) has limited effect. New treatments are needed, thus increased understanding of molecular disease mechanisms in IIM is required.
The overall aim of my thesis was to get an increased understanding of molecular mechanisms that are involved in IIM with a focus on the type I IFN system, autoantibodies and mechanisms that may induce immune reactivity, to be able to subclassify patients.
Several new observations were made. Firstly, we found that line blot is a suitable serological test in myositis and is a reliable alternative to more time-consuming assays such as immunoprecipitation (paper I). Secondly, we concluded that smoking is associated with IIM patients who are either anti-Jo-1 autoantibody and/or HLA-DRB1*03 positive (paper II). These associations point towards a gene-environment interaction in the pathogenesis for IIM. Thirdly, we found that a high IFN score was not only associated with the subset DM, as previously reported, and IBM, but also with autoantibody monospecificity against RNA-binding proteins or with autoantibody multispecificity (paper III). Furthermore, we identified IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood, which supports IFN-α as a possible target for therapy in these patients. Finally, we found that PM and DM are associated with dysregulation of endothelial progenitor cell (EPC) phenotype and function that may be attributed, at least in part, to aberrant IL-18 and type I IFN pathways (paper IV).
In conclusion, this thesis confirms a role of the type I IFN system in myositis, especially in subgroups of patients, based on their autoantibody status, and implicates a relationship between the type I IFN system and endothelial disruption. Furthermore, smoking may be a trigger in the pathogenesis of IIM in genetic susceptible persons. However, the implication of our findings to disease prognosis and treatment remain to be determined
Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease
BACKGROUND:
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.
METHODS:
We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.
RESULTS:
During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.
CONCLUSIONS:
Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)
Work technique training for patients with chronic pain in neck, shoulder and arm. A questionnaire pilot study after a comprehensive exercise-oriented rehabilitation program
Matavfall i butik : Analys av samhÀllsförÀndringar
Syftet med detta projekt var att öka förstĂ„elsen för hur förĂ€ndringar i samhĂ€llet kommer till och kan pĂ„verka de nationella miljökvalitetsmĂ„len. Studien fokuserar pĂ„ den förĂ€ndring som skett i svensk livsmedelshandel under det senaste decenniet i intresset för och fokus pĂ„ matavfall/matsvinn som en viktig miljöfrĂ„ga. Under den hĂ€r tiden har frĂ„gan om matavfall gĂ„tt frĂ„n en icke-frĂ„ga till en frĂ„ga i rampljuset, bĂ„de i samhĂ€llet i stort och i livsmedelshandeln. Men hur gick det till? Vilka faktorer och aktörer gjorde förĂ€ndringen möjlig? Vad har förĂ€ndringen i fokus lett till i form av Ă€ndrade praktiker och avfallsnivĂ„er? Kombinerade metoderFör att nĂ„ studiens övergripande syfte och besvara projektets forskningsfrĂ„gor har kvalitativa och kvantitativa metoder kombinerats. I studiens kvalitativa del gjordes en intervjustudie och en mediestudie. Intervjustudien utforskade olika aktörers upplevelse av vad som förĂ€ndrats och hur detta gĂ„tt till, genom intervjuer med experter och med utvalda butiker. Mediestudien undersökte hur stor frĂ„gan om matavfall frĂ„n butiker varit i tryckt media över tid, och hur den beskrivits i olika typer av press vid olika tidpunkter. I studiens kvantitativa del anvĂ€ndes avfallsdata frĂ„n kommunala avfallsregister för att validera och mĂ€ta pĂ„verkan av detta förĂ€ndrade fokus pĂ„ matavfall, samt tajming och hastighet pĂ„ förĂ€ndringen. VĂ„ra resultat har sedan analyserats med grund i den litteraturstudie som gjordes inom ramen för projektet. Utöver forskningslitteratur har vi studerat och kartlagt viktiga initiativ och rapporter under det senaste decenniet. MĂ„nga av vĂ„ra slutsatser Ă€r gemensamma med slutsatserna i de tvĂ„ regeringsuppdrag som genomförts under denna tid.Ăkad rapportering i media över tidMedieanalysen visar att rapporteringen kring matavfall/matsvinn ökat kraftigt i svensk media under den studerade perioden, bĂ„de i branschmedia och i allmĂ€n dagspress. I den allmĂ€nna lokala median (landsortspress) har antalet trĂ€ffar för ordet matsvinn ökat frĂ„n 22 Ă„r 2008 till 720 trĂ€ffar Ă„r 2017. Rapporteringens innehĂ„ll och fokus har förĂ€ndrats och utvecklats över tid. HĂ„rt generaliserat kan förĂ€ndringen beskrivas som att rapporteringen utvecklats frĂ„n att etablera matavfall/matsvinn som ett problem och resursslöseri genom publicering av statistik om dess omfattning (2008â2010) till ett stort miljö- och klimatproblem (2013) med fler ansvariga Ă€n endast konsumenter. FrĂ„n 2016 och framĂ„t framstĂ€lls frĂ„gan om matavfall/matsvinn i butik mer som ett gemensamt problem genom hela kedjan, frĂ„n producent till konsument sĂ„vĂ€l som för myndigheter och den politiska nivĂ„n. Rapporteringen över tid beskriver problemet och ger exempel pĂ„ goda initiativ och lösningar. Sektorsspecifik media följer ungefĂ€r samma tematiska utveckling över tid som dagspressen, men problematiserar i större utstrĂ€ckning om exempelvis ansvar i olika led i kedjan. Samverkande aktörer och faktorer lyfte frĂ„ganIntervjustudien visar pĂ„ ett antal viktiga faktorer och nyckelaktörer som samverkade för att sĂ€tta fokus pĂ„ frĂ„gan om matavfall i Sverige:âą MĂ€tningens roll för synliggörande av frĂ„ganâą Formeringen av aktörsnĂ€tverk (SaMMa) som kunde arbeta gemensamtâą Medias roll som nyckelaktör och nyckelstrategi i arbetet med frĂ„ganâą Ăkat fokus pĂ„ miljö- och klimatfrĂ„gor generellt i samhĂ€lletâą AttitydförĂ€ndring hos konsumenter och i branschenâą Digitalisering som givit nya verktyg och arbetssĂ€ttBĂ„de struktur och person har betydelse för nivĂ„ av matavfall Det rĂ„der samsyn i intervjustudien om den grundlĂ€ggande orsaken till matavfall: Matavfall Ă€r ett vĂ€lfĂ€rdsproblem som uppstĂ„r pĂ„ grund av att mat Ă€r för billigt. Intervjustudien visar pĂ„ betydelsen av handelns attityder och praktiker för mĂ€ngden matavfall i butik. Mycket av det som görs i butik har sitt ursprung i tankar om hur konsumenterna beter sig, och vad som genererar försĂ€ljning och inte. Olika butikschefer verkar göra mycket olika bedömningar av nĂ€r svinnets storlek motiverar en minskning/förĂ€ndring av utbud och sortiment. Butikschefens instĂ€llning till frĂ„gan Ă€r avgörande för vilket arbete med att minska matavfallet som bedrivs. Inköp/ bestĂ€llning ses som en nyckelfaktor i sammanhanget att minska matavfall medan lagstiftning och regelverk i mĂ„nga fall ses som ett hinder. DatummĂ€rkning och reglerna kring information för icke fĂ€rdigförpackad mat Ă€r exempel pĂ„ omrĂ„den som lyfts som problematiska. Incitament och prevention Ett intressant faktum som lyfts Ă€r att det i flera fall (sĂ€rskilt nĂ€r det gĂ€ller billiga varor som exempelvis bröd) kostar mer för butiker att genom arbetskrĂ€vande Ă„tgĂ€rder försöka sĂ€lja ut varan, Ă€n vad det gör att slĂ€nga den. I andra fall Ă€r/uppfattas förebyggande arbete som lönsamt, och Ă€r nĂ„got som mĂ„nga butiker arbetar aktivt med i olika utstrĂ€ckning. Att undersöka hur incitament för hur minskat matavfall i butikssektorn kan förstĂ€rkas, för att öka preventivt arbete i butik, Ă€r en viktig framtida uppgift för ansvariga myndigheter. Intervjustudien visar att i de fall matavfallet anvĂ€nds som resurs, till exempel till biogas eller till jĂ€st- eller ströbrödstillverkning, finns tendenser att se matavfallet som ett mindre problem. Detta kan göra att incitamenten minskar för att förebygga uppkomsten av matavfallet i tidigare skeden. Vikten av hela kedjanI intervjustudien lyfts vikten av att se till hela livsmedelskedjan â frĂ„n producent till konsument â nĂ€r man tittar pĂ„ hur matavfall kan motverkas. Hur affĂ€rsmodellen ser ut och pĂ„verkar samverkan och styrkeförhĂ„llanden mellan olika aktörer betraktas som en nyckelfrĂ„ga i bĂ„de butiks- och expertintervjuer. Analysen av resultaten gör gĂ€llande att denna frĂ„ga Ă€r en av de viktigare att arbeta med framöver. Idag finns en tendens att framstĂ€lla problemet som frĂ€mst nĂ„gon annans, i en annan del av kedjan. Kvantitativ studie â stora variationerStudien visar att det via kommunala avfallsregister i kommuner med viktbaserad avfallstaxa gĂ„r att fĂ„ fram data över mĂ€ngd avfall som butiker genererar; utsorterat matavfall och restavfall. Det var dock svĂ„righeter att ta fram uppgifter om totala mĂ€ngder matavfall eftersom det kan finnas matavfall i restavfallet. Det finns ocksĂ„ butiker som inte anvĂ€nder kommunal hĂ€mtning av matavfall och/eller restavfall. Kommunala avfallsregister ger dĂ€rmed inte en total tĂ€ckning av alla butiker. I vĂ„r studie var tĂ€ckningen 14 av 40 butiker. Det visar hur svĂ„rt det Ă€r att ta fram data över matavfall och visar pĂ„ behovet av andra datakĂ€llor, till exempel frĂ„n butiker som registrerar matsvinn. AvfallsmĂ€ngderna i de undersökta butikerna varierar mellan olika mĂ„nader, mellan olika Ă„r, mellan olika avfallsslag (restavfall, matavfall och Ă„tervinningsbart) och för total mĂ€ngd avfall mellan olika butiker. Avfallsdata gav ingen sĂ€ker trend pĂ„ grund av litet dataset och att matavfallets vĂ€g Ă€r mycket komplex med mĂ„nga aktörer, sĂ„vĂ€l kommunala som privata. De stora variationerna mellan butiker stĂ€rker den kvalitativa studiens resultat om butikschefernas betydelse för synen pĂ„, och arbetet med, att förebygga matavfall. Ett intressant resultat frĂ„n avfallsdata Ă€r att för de fyra butiker som undersökts nĂ€rmare i denna studie visar sig att de mindre butikerna genererar mindre avfall per kvadratmeter butiksyta jĂ€mfört med de större butikerna. Tidigare forskning har visat pĂ„ det omvĂ€nda för mĂ€ngd matavfall. Huruvida butiksytan i sig pĂ„verkar avfallsgenereringen per kvadratmeter borde testas i en större kvantitativ studie. Fler butiker kan ansluta sig till separat matavfallsinsamlingProjektet visar att alla butiker inte anvĂ€nder sig av separat matavfallsinsamling, varken via kommunen eller annan privat aktör, trots att det erbjuds. Att se till att matavfallet tas om hand och blir biogas och/eller kompost Ă€r viktigt och blir obligatoriskt senast 2023 enligt det kommande reviderade avfallsdirektivet. HĂ€r kan kommuner och privata aktörer fĂ„ fler att anvĂ€nda denna tjĂ€nst. Data frĂ„n kommunala avfallsregister visar att vissa butiker Ă€r snabba att anpassa sig och anvĂ€nder kommunal matavfallsinsamling sĂ„ snart den erbjuds.LĂ€rdomar att ta med sig till andra omrĂ„denMedias roll som bĂ„de katalysator, blĂ„slampa och motivationsfaktor (god PR) bör inte underskattas i fallet med matavfallsfrĂ„gans förĂ€ndring. Detta anvĂ€ndes av de aktörer som ville pĂ„verka i frĂ„gan â ett tillvĂ€gagĂ„ngssĂ€tt som förmodligen kan kopieras till andra omrĂ„den. Betydelsen av data för synliggörande, opinionsbildning, och samverkande samhĂ€llsförĂ€ndring i form av ökat miljöfokus i samhĂ€llet som smörjmedel för uppmĂ€rksamhet/attitydförĂ€ndring Ă€r förmodligen ocksĂ„ överförbart till andra frĂ„gor.
Variability in patient characteristics and service provision of interdisciplinary pain rehabilitation : A study using the Swedish national quality registry for pain rehabilitation
OBJECTIVE: To describe the organization, content and dosage of interdisciplinary pain rehabilitation, and the differences in degree of severity of problems of patients admitted to clinical units reporting to a Swedish national quality pain registry, grouped according to unit size and possible affiliation with a university hospital. METHODS: Reports from 31 out of 39 clinical units in Sweden, on inclusion processes, organization, content and dosage of interdisciplinary pain rehabilitation, and patient-reported data from a Swedish national quality pain registry at assessment for interdisciplinary pain rehabilitation were analysed. RESULTS: the number of patients treated annually at each unit ranged from 3 to 340. In 17 units, teams comprised 5 professionals. Dosage of interdisciplinary pain rehabilitation ranged from 20-180 h per patient in total. Patients at the university-hospital units scored the highest levels of symptoms and lowest levels of health-related quality of life. Units used similar sets of inclusion criteria, and several treatments, such as education, self-training and psychological interventions, were used by most units. CONCLUSION: When interpreting outcome data from registries, aspects other than rehabilitation outcomes must be considered. The interpretation of outcomes from quality registries would be facilitated if data, in addition to assessments and patient-reported outcomes, also includes standardized descriptions of the reporting clinical units
T-cell transcriptomics from peripheral blood highlights differences between polymyositis and dermatomyositis patients
Abstract Background Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies, a chronic inflammatory disorder clinically characterized by muscle weakness and inflammatory cell infiltrates in muscle tissue. In PM, a major component of inflammatory cell infiltrates is CD8+ T cells, whereas in DM, CD4+ T cells, plasmacytoid dendritic cells, and B cells predominate. In this study, with the aim to differentiate involvement of CD4+ and CD8+ T-cell subpopulations in myositis subgroups, we investigated transcriptomic profiles of T cells from peripheral blood of patients with myositis. Methods Total RNA was extracted from CD4+ T cells (PMâ=â8 and DMâ=â7) and CD8+ T cells (PMâ=â4 and DMâ=â5) that were isolated from peripheral blood mononuclear cells via positive selection using microbeads. Sequencing libraries were generated using the Illumina TruSeq Stranded Total RNA Kit and sequenced on an Illumina HiSeq 2500 platform, yielding about 50 million paired-end reads per sample. Differential gene expression analyses were conducted using DESeq2. Results In CD4+ T cells, only two genes, ANKRD55 and S100B, were expressed significantly higher in patients with PM than in patients with DM (false discovery rate [FDR]â<â0.05, model adjusted for age, sex, HLA-DRB1 *03 status, and RNA integrity number [RIN]). On the contrary, in CD8+ T cells, 176 genes were differentially expressed in patients with PM compared with patients with DM. Of these, 44 genes were expressed significantly higher in CD8+ T cells from patients with PM, and 132 genes were expressed significantly higher in CD8+ T cells from patients with DM (FDRâ<â0.05, model adjusted for age, sex, and RIN). Gene Ontology analysis showed that genes differentially expressed in CD8+ T cells are involved in lymphocyte migration and regulation of T-cell differentiation. Conclusions Our data strongly suggest that CD8+ T cells represent a major divergence between PM and DM patients compared with CD4+ T cells. These alterations in the gene expression in T cells from PM and DM patients might advocate for distinct immune mechanisms in these subphenotypes of myositis
Serum levels of B-cell activating factor of the TNF family (BAFF) correlate with anti-Jo-1 autoantibodies levels and disease activity in patients with anti-Jo-1positive polymyositis and dermatomyositis
Abstract Background B-cell activating factor of the tumour necrosis factor family (BAFF) plays a role in autoantibody production and is elevated in dermatomyositis (DM) and anti-Jo-1-positive polymyositis (PM). We investigated the inter-relationships between serum levels of BAFF, anti-Jo-1 autoantibodies, and disease activity. Methods Serum levels of BAFF and anti-Jo-1 antibodies measured by enzyme-linked immunosorbent assay (ELISA) were compared to levels of myoglobin, creatine kinase (CK), aminotransferases (alanine (ALT) and aspartate (AST)), C-reactive protein (CRP), and disease activity assessed by the Myositis Disease Activity Assessment Tool in 63 anti-Jo-1 antibody-positive DM/PM patients. Serial serum samples collected at 2 (46 cases) and 3â5 time points (23 cases) were included. Relationships between BAFF, anti-Jo-1, disease activity, CRP, and their longitudinal changes were evaluated using correlation analysis, multiple regression (MR), path analysis (PA), and hierarchical linear models (HLM). Results Cross-sectional assessment demonstrated significant correlations between the levels of BAFF and anti-Jo-1 antibodies which were associated with levels of CK, myoglobin, AST, and CRP, as well as multivariate associations between BAFF, anti-Jo-1 antibodies, and CK levels. PA revealed direct effects of anti-Jo-1 antibodies on CK (ÎČâ=â0.41) and both direct (ÎČâ=â0.42) and indirect (through anti-Jo-1 antibodies; ÎČâ=â0.17) effects of BAFF on CK. Changes in levels of both BAFF and anti-Jo-1 between two time points (Î) were associated with Îmyoglobin and Îaminotransferases and changes of BAFF correlated with ÎCK, Îcutaneous, Îmuscle, Îglobal, and Îskeletal disease activities. The longitudinal analysis showed a high intra-individual variability of serum levels of BAFF over time (97%) which could predict 79% of the variance in anti-Jo-1 levels. The anti-Jo-1 variability was explained by inter-individual differences (68%). The close longitudinal relationship between levels of BAFF, anti-Jo-1, and disease activity was supported by high proportions of their variance explained with serum levels of CK and CRP or pulmonary and muscle activities. Conclusion Our findings of associations between levels of BAFF and anti-Jo-1 antibodies in serum and myositis activity suggest a role of this cytokine in disease-specific autoantibody production as part of disease mechanisms, and support BAFF as a potential target for intervention in anti-Jo-1-positive myositis patients