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1.
  • Abate, Michele, et al. (författare)
  • Pathogenesis of tendinopathies: inflammation or degeneration?
  • 2009
  • Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:3
  • Tidskriftsartikel (refereegranskat)abstract
    • The intrinsic pathogenetic mechanisms of tendinopathies are largely unknown and whether inflammation or degeneration has the prominent role is still a matter of debate. Assuming that there is a continuum from physiology to pathology, overuse may be considered as the initial disease factor; in this context, microruptures of tendon fibers occur and several molecules are expressed, some of which promote the healing process, while others, including inflammatory cytokines, act as disease mediators. Neural in-growth that accompanies the neovessels explains the occurrence of pain and triggers neurogenic-mediated inflammation. It is conceivable that inflammation and degeneration are not mutually exclusive, but work together in the pathogenesis of tendinopathies.
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2.
  • af Klint, Erik, et al. (författare)
  • Evaluation of arthroscopy and macroscopic scoring.
  • 2009
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:3
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Arthroscopy is a minimally invasive technique for retrieving synovial biopsies in rheumatology during the past 20 years. Vital for its use is continual evaluation of its safety and efficacy. Important for sampling is the fact of intraarticular variation for synovial markers. For microscopic measurements scoring systems have been developed and validated, but for macroscopic evaluations there is a need for further comprehensive description and validation of equivalent scoring systems.METHODS: We studied the complication rate and yield of arthroscopies performed at our clinic between 1998 and 2005. We also created and evaluated a macroscopic score set of instructions for synovitis.RESULTS: Of 408 procedures, we had two major and one minor complication; two haemarthrosis and one wound infection, respectively. Pain was most often not a problem, but 12 procedures had to be prematurely ended due to pain. Yield of biopsies adequate for histology were 83% over all, 94% for knee joints and 34% for smaller joints. Video printer photographs of synovium taken during arthroscopy were jointly and individually reviewed by seven raters in several settings, and intra and inter rater variation was calculated. A macroscopic synovial scoring system for arthroscopy was created (Macro-score), based upon hypertrophy, vascularity and global synovitis. These written instructions were evaluated by five control-raters, and when evaluated individual parameters were without greater intra or inter rater variability, indicating that the score is reliable and easy to use.CONCLUSIONS: In our hands rheumatologic arthroscopy is a safe method with very few complications. For knee joints it is a reliable method to retrieve representative tissue in clinical longitudinal studies. We also created an easy to use macroscopic score, that needs to be validated against other methodologies. We hope it will be of value in further developing international standards in this area.
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3.
  • Ahlqvist, Emma, et al. (författare)
  • The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis.
  • 2009
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:3
  • Forskningsöversikt (refereegranskat)abstract
    • ABSTRACT: For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future.
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5.
  • Ajeganova, Sofia, et al. (författare)
  • Higher levels of anti-phosphorylcholine autoantibodies in early rheumatoid arthritis indicate lower risk of incident cardiovascular events
  • 2021
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The increased risk of cardiovascular events (CVE) in rheumatoid arthritis (RA) is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. It has been suggested that anti-phosphorylcholine antibodies (anti-PC) of the IgM subclass may have atheroprotective effects. Here, we aimed to investigate the association between levels of IgM anti-PC antibodies with CVE in patients with early RA. Methods: The study population was derived from the BARFOT early RA cohort, recruited in 1994–1999. The outcome of incident CVE (AMI, angina pectoris, coronary intervention, ischemic stroke, TIA) was tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM. The Kaplan-Meier estimates and Cox proportional hazards regression models were used to compare CV outcome in the groups categorized by baseline median level of IgM anti-PC. Results: In all, 653 patients with early RA, 68% women, mean (SD) age 54.8 (14.7) years, DAS28 5.2 (1.3), 68% seropositive, and without prevalent CVD, were included. During the follow-up of mean 11.7 years, 141 incident CVE were recorded. Baseline IgM anti-PC above median was associated with a reduction in risk of incident CVE in patients aged below 55 years at inclusion, HR 0.360 (95% CI, 0.142–0.916); in males, HR 0.558 (0.325–0.958); in patients with BMI above 30 kg/m2, HR 0.235 (0.065–0.842); and in those who did not achieve DAS28 remission at 1 year, HR 0.592 (0.379–0.924). The pattern of associations was confirmed in the models with AUC IgM anti-PC over 2 years. Conclusion: Protective effects of higher levels of innate IgM anti-PC autoantibodies on CVE were detected in younger patients with RA and those at high risk of CVE: males, presence of obesity, and non-remission at 1 year.
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6.
  • Aldridge, Jonathan, et al. (författare)
  • Sex-based differences in association between circulating T cell subsets and disease activity in untreated early rheumatoid arthritis patients
  • 2018
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 20:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It is not known if sex-based disparities in immunological factors contribute to the disease process in rheumatoid arthritis (RA). Hence, we examined whether circulating T cell subset proportions and their association with disease activity differed in male and female patients with untreated early rheumatoid arthritis (ueRA). Methods: Proportions of T cell subsets were analyzed in peripheral blood from 72 ueRA DMARD-and corticosteroid-naive patients (50 females and 22 males) and in 31 healthy age-and sex-matched controls. Broad analysis of helper and regulatory CD4(+) T cell subsets was done using flow cytometry. Disease activity in patients was assessed using DAS28, CDAI, swollen joint counts, tender joint counts, CRP, and ESR. Results: Multivariate factor analyses showed that male and female ueRA patients display distinct profiles of association between disease activity and circulating T cell subset proportions. In male, but not female, ueRA patients Th2 cells showed a positive association with disease activity and correlated significantly with DAS28-ESR, CDAI, and swollen and tender joint counts. Likewise, proportions of non-regulatory CTLA-4(+) T cells associated positively with disease activity in male patients only, and correlated with DAS28-ESR. In contrast, there was a negative relation between Th1Th17 subset proportions and disease activity in males only. The proportions of Th17 cells correlated positively with DAS28-ESR in males only, while proportions of Th1 cells showed no relation to disease activity in either sex. There were no significant differences in proportions of T cell subsets between the sexes in patients with ueRA. Conclusions: Our findings show sex-based differences in the association between T cell subsets and disease activity in ueRA patients, and that Th2 helper T cells may have a role in regulating disease activity in male patients.
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7.
  • Aldridge, Jonathan, et al. (författare)
  • T helper cells in synovial fluid of patients with rheumatoid arthritis primarily have a Th1 and a CXCR3(+)Th2 phenotype
  • 2020
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The majority of CD4(+)T helper (Th) cells found in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) express CXCR3, a receptor associated with Th1 cells. In blood, subsets of Th2 and Th17 cells also express CXCR3, but it is unknown if these cells are present in RA SF or how cytokines from these subsets affect cytokine/chemokine secretion by fibroblast-like synoviocytes (FLS) from patients with RA. Methods We examined the proportions of Th1, Th2, CXCR3(+)Th2, Th17, CXCR3(+)Th17, Th1Th17, peripheral T helper (TPh) and T follicular helper (TFh) cells in paired SF and blood, as well as the phenotype of TPh and TFh cells in RA SF (n = 8), by the use of flow cytometry. We also examined the cytokine/chemokine profile in paired SF and plasma (n = 8) and in culture supernatants of FLS from patients with chronic RA (n = 7) stimulated with Th-associated cytokines, by the use of cytometric bead arrays and ELISA. Cytokine receptor expression in FLS (n = 3) were assessed by the use of RNA sequencing and qPCR. Results The proportions of Th1 and CXCR3(+)Th2 cells were higher in SF than in blood (P < 0.05). TPh and PD-1(high)TFh in RA SF were primarily of a Th1 and a CXCR3(+)Th2 phenotype. Moreover, the levels of CXCL9, CXCL10, CCL20, CCL2, CXCL8, IL-6 and IL-10 were higher in SF than in plasma (P < 0.05). Lastly, IL-4, IL-13 and IL-17A induced RA FLS to secrete proinflammatory IL-6, CCL2, CXCL1 and CXCL8, while IFN gamma mainly induced CXCL10. Conclusion These findings indicate that not only Th1 but also CXCR3(+)Th2 cells may have a pathogenic role in RA synovial inflammation.
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8.
  • Almehed, Katarina, 1966, et al. (författare)
  • Prevalence and risk factors of vertebral compression fractures in female SLE patients.
  • 2010
  • Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 12:4
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT: INTRODUCTION: Our objective was to determine the frequency of and factors associated with prevalent vertebral compression fractures in female SLE patients attending rheumatologists in Western Sweden. METHODS: In this cross sectional study 150 women were included. They were examined with x-ray of thoracic and lumbar spine (Th4-L4). A reduction of at least 20% of any vertebral height, assessed by Genant's semiquantitative method, was defined as a fracture. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA). RESULTS: Median patient age was 47 years (20-82) and disease duration 11 years (1-41). Only 6 (4%) women had a history of clinical compressions whereas 43 (29%) had at least one radiological fracture each. The patients with at least one fracture at any site were characterized by higher age (p<0.001), being postmenopausal (p<0.01), higher Systemic Lupus International Collaborative Clinics Damage Index (p<0.05), lower BMD total hip and femoral neck (p<0.05), more peripheral fractures (p< 0.01), medication with bisphosphonates (p<0.05) and calcium and vitamin D3 (p<0.05). There were no significant differences regarding current or cumulative glucocorticosteroid dose between the groups. In logistic regression analyses high age remained as risk factor of at least one vertebral fracture at any site whereas low BMD in total hip was associated with vertebral fracture in lumbar spine. CONCLUSION: Radiological compression fractures are common but seldom diagnosed in SLE patients. High age and low BMD in total hip, but not in spine, was associated with vertebral fractures.
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9.
  • Almehed, Katarina, 1966, et al. (författare)
  • Role of resistin as a marker of inflammation in systemic lupus erythematosus.
  • 2008
  • Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Resistin is a cystein-rich secretory adipokine. It is proposed to have proinflammatory properties in humans. The aim of this study was to determine associations between serum levels of resistin and markers of inflammation and bone mineral density (BMD) in female patients with systemic lupus erythematosus (SLE). METHODS: One hundred sixty-three female patients with SLE (20 to 82 years old) were examined in a cross-sectional study. Venous blood samples were analyzed for resistin, erythrocyte sedimentation rate (ESR), C-reactive protein, creatinine, fasting lipids, complements, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, sIL-6R (soluble IL-6 receptor), ICTP (C-terminal telopeptide of type I collagen), and PINP (N-terminal propeptide of type I procollagen). Simple and multiple regression analyses as well as logistic regression analyses were performed. Resistin in serum was compared with 42 healthy female controls with respect to age. RESULTS: Serum resistin levels in controls were similar to those of patients with SLE. Markers of inflammation and current dose of glucocorticosteroids correlated positively to resistin in serum. Markers of renal function, number of prevalent vertebral fractures, and BMD were also significantly associated with resistin. In a multiple regression model, ESR, creatinine, C3, current glucocorticosteroid dose, high-density lipoprotein, and BMD radius remained significantly associated with resistin. In logistic regression analyses with resistin as the independent variable, a significant association was found with ESR (normal or elevated) but not with S-creatinine or z score for hip and radius total. CONCLUSION: Although resistin measurements did not differ between patients and controls, resistin was clearly associated with general inflammation, renal disease, treatment with glucocorticosteroids, and bone loss. We hypothesize that resistin has proinflammatory and disease-promoting properties in SLE. Further studies are needed to elucidate the mechanism behind these associations.
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12.
  • Andersson, Lars, 1977, et al. (författare)
  • A web tool for finding gene candidates associated with experimentally induced arthritis in the rat
  • 2005
  • Ingår i: Arthritis Res Ther. - : BioMed Central Ltd.. ; 7:3, s. R485-R492
  • Tidskriftsartikel (refereegranskat)abstract
    • Rat models are frequently used for finding genes contributing to the arthritis phenotype. In most studies, however, limitations in the number of animals result in a low resolution. As a result, the linkage between the autoimmune experimental arthritis phenotype and the genomic region, that is, the quantitative trait locus, can cover several hundred genes. The purpose of this work was to facilitate the search for candidate genes in such regions by introducing a web tool called Candidate Gene Capture (CGC) that takes advantage of free text data on gene function. The CGC tool was developed by combining genomic regions in the rat, associated with the autoimmune experimental arthritis phenotype, with rat/human gene homology data, and with descriptions of phenotypic gene effects and selected keywords. Each keyword was assigned a value, which was used for ranking genes based on their description of phenotypic gene effects. The application was implemented as a web-based tool and made public at http://ratmap.org/cgc. The CGC application ranks gene candidates for 37 rat genomic regions associated with autoimmune experimental arthritis phenotypes. To evaluate the CGC tool, the gene ranking in four regions was compared with an independent manual evaluation. In these sample tests, there was a full agreement between the manual ranking and the CGC ranking for the four highest-ranked genes in each test, except for one single gene. This indicates that the CGC tool creates a ranking very similar to that made by human inspection. The exceptional gene, which was ranked as a gene candidate by the CGC tool but not in the manual evaluation, was found to be closely associated with rheumatoid arthritis in additional literature studies. Genes ranked by the CGC tools as less likely gene candidates, as well as genes ranked low, were generally rated in a similar manner to those done manually. Thus, to find genes contributing to experimentally induced arthritis, we consider the CGC application to be a helpful tool in facilitating the evaluation of large amounts of textual information.
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13.
  • Andersson, Martin K, et al. (författare)
  • Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients.
  • 2007
  • Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Aseptic loosening of a joint prosthesis is associated with remodelling of bone tissue in the vicinity of the prosthesis. In the present study, we investigated the effects of synovial fluid (SF) from patients with a loose prosthetic component and periprosthetic osteolysis on osteoclast and osteoblast activities in vitro and made comparisons with the effects of SF from patients with osteoarthritis (OA). Bone resorption was assessed by the release of calcium 45 (45Ca) from cultured calvariae. The mRNA expression in calvarial bones of molecules known to be involved in osteoclast and osteoblast differentiation was assessed using semi-quantitative reverse transcription-polymerase chain reaction (PCR) and real-time PCR. SFs from patients with a loose joint prosthesis and patients with OA, but not SFs from healthy subjects, significantly enhanced 45Ca release, effects associated with increased mRNA expression of calcitonin receptor and tartrate-resistant acid phosphatase. The mRNA expression of receptor activator of nuclear factor-kappa-B ligand (rankl) and osteoprotegerin (opg) was enhanced by SFs from both patient categories. The mRNA expressions of nfat2 (nuclear factor of activated T cells 2) and oscar (osteoclast-associated receptor) were enhanced only by SFs from patients with OA, whereas the mRNA expressions of dap12 (DNAX-activating protein 12) and fcrgamma (Fc receptor common gamma subunit) were not affected by either of the two SF types. Bone resorption induced by SFs was inhibited by addition of OPG. Antibodies neutralising interleukin (IL)-1alpha, IL-1beta, soluble IL-6 receptor, IL-17, or tumour necrosis factor-alpha, when added to individual SFs, only occasionally decreased the bone-resorbing activity. The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis. Our findings demonstrate the presence of a factor (or factors) stimulating both osteoclast and osteoblast activities in SFs from patients with a loose joint prosthesis and periprosthetic osteolysis as well as in SFs from patients with OA. SF-induced bone resorption was dependent on activation of the RANKL/RANK/OPG pathway. The bone-resorbing activity could not be attributed solely to any of the known pro-inflammatory cytokines, well known to stimulate bone resorption, or to RANKL or prostaglandin E2 in SFs. The data indicate that SFs from patients with a loose prosthesis or with OA stimulate bone resorption and that SFs from patients with OA are more prone to enhance bone formation.
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  • Andréasson, Kristofer, et al. (författare)
  • Faecal levels of calprotectin in systemic sclerosis are stable over time and are higher compared to primary Sjogren's syndrome and rheumatoid arthritis
  • 2014
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Faecal calprotectin (FC) has been proposed to be a biomarker of gastrointestinal (GI) disease in systemic sclerosis (SSc). The purpose of this study was to extend cross-sectional observations and prospectively assess the variability of FC over time in SSc patients. We also aimed to examine FC in relation to immunosuppressive therapy. Finally we wanted to analyse FC in other rheumatic diseases to evaluate the specificity of FC for SSc GI disease. Methods: FC was measured in consecutive patients with SSc, primary Sjogren's syndrome (pSS), rheumatoid arthritis (RA) and in healthy hospital workers. The intraindividual variability of FC in SSc was assessed with intra class correlation (ICC) and. statistics. Associations between FC and objective markers of GI disease and immunosuppressive medication were investigated. Results: FC was associated with micronutrient deficiency and GI pathology as assessed by cineradiography confirming our previous results. FC showed only a limited intra-individual variation in SSc, ICC = 0.69 (95% confidence interval, CI: 0.57-0.78) and kappa = 0.64 (95% CI: 0.56-0.73). Generalised immunosuppression did not have any significant impact on FC. FC was significantly higher in SSc patients compared to patients with pSS or RA as well as compared to healthy subjects. Conclusions: FC is a promising non-invasive biomarker for GI disease in SSc. In view of stable levels over time, FC could be a useful marker when novel, more specific drugs targeting the GI tract in SSc will be introduced.
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16.
  • Andréasson, Kristofer, et al. (författare)
  • Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease
  • 2016
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Recent evidence suggests a link between autoimmunity and the intestinal microbial composition in several rheumatic diseases including systemic sclerosis (SSc). The objective of this study was to investigate the prevalence of intestinal dysbiosis in SSc and to characterise patients suffering from this potentially immunomodulatory deviation. Methods: This study consisted of 98 consecutive patients subject to in-hospital care. Stool samples were analysed for intestinal microbiota composition using a validated genome-based microbiota test (GA-map™ Dysbiosis Test, Genetic Analysis, Oslo, Norway). Gut microbiota dysbiosis was found present as per this standardised test. Patients were examined regarding gastrointestinal and extraintestinal manifestations of SSc by clinical, laboratory, and radiological measures including esophageal cineradiography, the Malnutrition Universal Screening Tool (MUST), levels of plasma transthyretin (a marker of malnutrition) and faecal (F-) calprotectin (a marker of intestinal inflammation). Results: A majority (75.5%) of the patients exhibited dysbiosis. Dysbiosis was more severe (rs=0.31, p=0.001) and more common (p=0.013) in patients with esophageal dysmotility. Dysbiosis was also more pronounced in patients with abnormal plasma levels of transthyretin (p=0.045) or micronutrient deficiency (p=0.009). In 19 patients at risk for malnutrition according to the MUST, 18 exhibited dysbiosis. Conversely, of the 24 patients with a negative dysbiosis test, only one was at risk for malnutrition. The mean±SEM levels of F-calprotectin were 112±14 and 45±8μg/g in patients with a positive and negative dysbiosis test, respectively. Dysbiosis was more severe in patients with skin telangiectasias (p=0.020), pitting scars (p=0.023), pulmonary fibrosis (p=0.009), and elevated serum markers of inflammation (p<0.001). However, dysbiosis did not correlate with age, disease duration, disease subtype, or extent of skin fibrosis. Conclusions: In this cross-sectional study, intestinal dysbiosis was common in patients with SSc and was associated with gastrointestinal dysfunction, malnutrition and with some inflammatory, fibrotic and vascular extraintestinal features of SSc. Further studies are needed to elucidate the potential causal relationship of intestinal microbe-host interaction in this autoimmune disease.
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17.
  • Andréasson, Kristofer, et al. (författare)
  • Mycophenolate mofetil for systemic sclerosis : drug exposure exhibits considerable inter-individual variation-a prospective, observational study
  • 2020
  • Ingår i: Arthritis Research & Therapy. - : BMC. - 1478-6362 .- 1478-6354. ; 22
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs.Methods: This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5g twice daily since at least 3months. The 12-h drug exposure of the active MMF metabolite mycophenolic acid (MPA) was estimated by repeated analysis of plasma MPA over a 6-h period. This 12-h drug exposure was dose normalised to a daily intake of 3g MMF (MPA_AUC(3g)) in order to compare subjects using MMF at different doses. Drug exposure was analysed in reference to the clinical characteristics including body weight, renal function, autoantibodies, intestinal dysbiosis, intestinal inflammation assessed by faecal (F)-calprotectin, intestinal symptoms assessed by the University of California Los Angeles Scleroderma Trial Consortium Gastrointestinal Tract Instrument 2.0 and concomitant drug usage including proton-pump inhibitors (PPI).Results:Thirty-four out of 35 study participants completed the study. The mean daily MMF dose was 2.1g. Drug exposure expressed as MPA_AUC(3g) varied up to 8-fold between patients (median 115, range 27-226mg h/L).MPA_AUC(3g) was inversely related to body weight (r(s)=-0.58, p<0.001) and renal function (r(s)=-0.34, p=0.054). Anti-topoisomerase-1 antibodies and male sex were associated with lower MPA_AUC(3g) (87 vs 123 and 71 vs 141; p=0.008 and p=0.015, respectively). MPA_AUC(3g) was inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (r(s)=-0.54, p=0.004; r(s)=-0.36, p=0.034), but not to gastrointestinal symptoms. MPA_AUC(3g) was inversely related to PPI usage (r(s)=-0.45, p=0.007). We found no association between MPA_AUC(3g) and disease subtype, disease duration or disease activity.Conclusion: MMF-treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc.
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18.
  • Arve-Butler, Sabine, et al. (författare)
  • Synovial fluid neutrophils in oligoarticular juvenile idiopathic arthritis have an altered phenotype and impaired effector functions
  • 2021
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Neutrophils are the most prevalent immune cells in the synovial fluid in inflamed joints of children with oligoarticular juvenile idiopathic arthritis (JIA). Despite this, little is known about neutrophil function at the site of inflammation in JIA and how local neutrophils contribute to disease pathogenesis. This study aimed to characterize the phenotype and function of synovial fluid neutrophils in oligoarticular JIA. Methods: Neutrophils obtained from paired blood and synovial fluid from patients with active oligoarticular JIA were investigated phenotypically (n = 17) and functionally (phagocytosis and oxidative burst, n = 13) by flow cytometry. In a subset of patients (n = 6), blood samples were also obtained during inactive disease at a follow-up visit. The presence of CD206-expressing neutrophils was investigated in synovial biopsies from four patients by immunofluorescence. Results: Neutrophils in synovial fluid had an activated phenotype, characterized by increased CD66b and CD11b levels, and most neutrophils had a CD16hi CD62Llowaged phenotype. A large proportion of the synovial fluid neutrophils expressed CD206, a mannose receptor not commonly expressed by neutrophils but by monocytes, macrophages, and dendritic cells. CD206-expressing neutrophils were also found in synovial tissue biopsies. The synovial fluid neutrophil phenotype was not dependent on transmigration alone. Functionally, synovial fluid neutrophils had reduced phagocytic capacity and a trend towards impaired oxidative burst compared to blood neutrophils. In addition, the effector functions of the synovial fluid neutrophils correlated negatively with the proportion of CD206+ neutrophils. Conclusions: Neutrophils in the inflamed joint in oligoarticular JIA were altered, both regarding phenotype and function. Neutrophils in the synovial fluid were activated, had an aged phenotype, had gained monocyte-like features, and had impaired phagocytic capacity. The impairment in phagocytosis and oxidative burst was associated with the phenotype shift. We speculate that these neutrophil alterations might play a role in the sustained joint inflammation seen in JIA.
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19.
  • Bajtner, Estelle, et al. (författare)
  • Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen
  • 2005
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7, s. R1148-R1157
  • Tidskriftsartikel (refereegranskat)abstract
    • Antibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/cxB10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/cxB10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.
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21.
  • Bauer, K, et al. (författare)
  • Perforin deficiency attenuates collagen-induced arthritis
  • 2005
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:4, s. 877-884
  • Tidskriftsartikel (refereegranskat)abstract
    • Collagen-induced arthritis ( CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8(+) T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8(+) T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp(-/-), and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp(+/+), 64%; DBA/1J-pfp(-/-), 54%), a slightly delayed onset ( onset of disease: DBA/1J-pfp(+/+), 53 +/- 3.6; DBA/1J-pfp(-/-), 59 +/- 4.9 ( mean SEM), and milder form of the disease ( maximum disease score: DBA/1J-pfp(+/+), 7.3 +/- 1.1; DBA/1J-pfp(-/-), 3.4 +/- 1.4 ( mean SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp(-/-) mice compared with pfp(+/+) mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA.
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22.
  • Bengtsson, Anders A., et al. (författare)
  • Neutrophil FcγRIIA availability is associated with disease activity in systemic lupus erythematosus
  • 2020
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 22
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Immune complexes (ICs) are detectable in a variety of inflammatory diseases, including systemic lupus erythematosus (SLE), reflecting autoantibody binding to antigens. Though ICs are the main contributors to disease pathogenesis through FcγR-mediated inflammation and organ damage, IC levels are not part of the clinical assessment of SLE. The aim of this study was to explore the clinical utility of analyzing levels of ICs in SLE patients using a novel technology, IC-FLOW. Methods: Paired serum samples, at the time point of high and low disease activity (n = 92), were analyzed using two assays: an IC ELISA from a commercial company and a novel in-house flow cytometry-based method, IC-FLOW. IC-FLOW measures FcγRIIA availability on the neutrophil cell surface by flow cytometry, whereas the commercial ELISA measures IC binding to C1q. Results: Using IC-FLOW, 90% of SLE patients with active disease had elevated levels of circulating ICs (p < 0.0001). Using the commercial assay, only 17% of SLE patients had elevated levels of circulating ICs. For both assays, levels of ICs reflected active disease as determined by SLEDAI (r = 0.45, p < 0.0001) and were associated with type I IFN activity (r = 0.37, p = 0.001), and complement consumption (p = 0.0002). Levels of ICs measured with IC-FLOW, but not with the commercial ELISA, were associated with active lupus nephritis (p = 0.004). Conclusions: This novel FcγRIIA-IC assay can detect levels of circulating ICs in patients with SLE. Analyzing IC levels may facilitate monitoring of disease activity, as well as identify patients at risk of lupus nephritis, allowing for early preventive interventions.
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23.
  • Bengtsson, Anders, et al. (författare)
  • Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus
  • 2014
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE. Methods: The following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli (E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bone marrow, defined as percentage of CD10(-)D16(low) in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR. Results: SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10(-)CD16(low) phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation. Conclusions: Our results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.
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24.
  • Bengtsson, Karin, 1980, et al. (författare)
  • Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study
  • 2017
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: To investigate the risk of first-time acute coronary syndrome (ACS), stroke and venous thromboembolism (VTE) in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA) and undifferentiated spondyloarthritis (uSpA), compared to each other and to the general population (GP). Methods: This is a prospective nationwide cohort study. Cohorts with AS (n = 6448), PsA (n = 16,063) and uSpA (n = 5190) patients and a GP (n = 266,435) cohort, were identified 2001-2009 in the Swedish National Patient and Population registers. The follow-up began 1 January 2006, or 6 months after the first registered spondyloarthritis (SpA) diagnosis thereafter, and ended at ACS/stroke/VTE event, death, emigration or 31 December 2012. Crude and age- and sex-standardized incidence rates (SIRs) and hazard ratios (HRs) were calculated for incident ACS, stroke or VTE, respectively. Results: Standardized to the GP cohort, SIRs for ACS were 4.3, 5.4 and 4.7 events per 1000 person-years at risk in the AS, PsA and uSpA cohort, respectively, compared to 3.2 in the GP cohort. SIRs for stroke were 5.4, 5.9 and 5.7 events per 1000 person-years at risk in the AS, PsA and uSpA cohort compared to 4.7 in the GP cohort. Corresponding SIRs for VTE were 3.6, 3.2 and 3.5 events per 1000 person-years at risk compared to 2.2 in the GP cohort. Age-and sex-adjusted HRs (95% CI) for ACS events were significantly increased in AS (1.54 (1.31-1.82)), PsA (1.76 (1.59-1.95)) and uSpA (1.36 (1.05-1.76)) compared to GP. Age-adjusted HRs for ACS was significantly decreased in female AS patients (0.59 (0.37-0.97)) compared to female PsA patients. Age-and sex-adjusted HRs for stroke events were significantly increased in AS (1.25 (1.06-1.48)) and PsA (1.34 (1.22-1.48)), and nonsignificantly increased in uSpA (1.16 (0.91-1.47)) compared to GP. For VTE the age-and sex-adjusted HRs for AS, PsA and uSpA were equally and significantly increased with about 50% compared to GP. Conclusions: Patients with AS, PsA and uSpA are at increased risk for ACS and stroke events, which emphasizes the importance of identification of and intervention against cardiovascular risk factors in SpA patients. Increased alertness for VTE is warranted in patients with SpA.
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25.
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26.
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27.
  • Bergström, Beatrice, et al. (författare)
  • Methotrexate inhibits effects of platelet-derived growth factor and interleukin-1β on rheumatoid arthritis fibroblast-like synoviocytes
  • 2018
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 20:49
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A key feature of joints in rheumatoid arthritis (RA) is the formation of hyperplastic destructive pannus tissue, which is orchestrated by activated fibroblast-like synoviocytes (FLS). We have demonstrated that the RA risk gene and tumor suppressor Limb bud and heart development (LBH) regulates cell cycle progression in FLS. Methotrexate (MTX) is the first-line treatment for RA, but its mechanisms of action remain incompletely understood. Here, we studied the effects of MTX on mitogen-induced FLS proliferation and expression of cell cycle regulators in vitro. Methods: Primary FLS from patients with RA or osteoarthritis were stimulated with the mitogen platelet-derived growth factor (PDGF) and the cytokine interleukin-1β (IL-1β) in the presence or absence of MTX. Cells were then subjected to qPCR for gene expression and cell cycle analysis by flow cytometry. Results: Stimulation with PDGF and IL-1β increased the percentage of FLS in the G2/M phase and shifted the cell morphology to a dendritic shape. These effects were inhibited by MTX. Furthermore, PDGF + IL-1β reduced LBH mRNA expression. However, MTX treatment yielded significantly higher transcript levels of LBH, and of CDKN1A (p21) and TP53 (p53), compared to untreated samples upon mitogen stimulation. The expression of DNA methyltransferase-1 (DNMT1) was also higher in the presence of MTX and there was strong correlation between DNMT1 and LBH expression. Conclusions: Therapeutic concentrations of MTX abolish the effects of PDGF and IL-1β on tumor suppressor expression and inhibit mitogen-promoted FLS proliferation. These data demonstrate novel and important effects of MTX on pathogenic effector cells in the joint, which might involve epigenetic mechanisms. © 2018 The Author(s).
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28.
  • Berthold, Elisabet, et al. (författare)
  • Outcome in Juvenile Idiopathic arthritis : a population-based study from Sweden
  • 2019
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 21, s. 1-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: As the treatment arsenal for children with juvenile idiopathic arthritis (JIA) has expanded during the last decades, follow-up studies are needed on children diagnosed in the era of biological treatment to evaluate if this has improved the outcome. Our aim was to study the epidemiology and outcome of JIA in southern Sweden using a population-based cohort of children with a validated diagnosis of JIA collected over 9 years. Methods: Potential cases of JIA between 2002 and 2010 were collected after a database search, using the ICD codes M08-M09. The study area was Skåne, the southernmost county of Sweden (population 1.24 million; 17.6% aged < 16 years). The JIA diagnosis was validated and subcategorized through medical record review based on the criteria defined by the International League of Associations for Rheumatism (ILAR). Parameters on disease activity and pharmacologic treatment were recorded annually until the end of the study period (December 31, 2015). Results: In total, 251 cases of JIA were confirmed. The mean annual incidence rate for JIA was estimated to be 12.8/100,000 children < 16 years, with the highest age-specific annual incidence at the age of 2 years (36/100,000). Oligoarthritis was the largest subgroup (44.7%), and systemic JIA was the smallest subgroup (2.8%). Methotrexate was the most common disease-modifying anti-rheumatic drug prescribed (60.6%). Tumor necrosis factor alpha inhibitors were used as treatment for 23.9% of the children. Only 40.0% of the follow-up years, with a median follow-up time of 8 years, were free of arthritis or uveitis. Uveitis occurred in 10.8% of the children (8.0% chronic uveitis), and the need for joint corrective orthopedic surgery was 9.2%. Conclusions: The incidence of JIA in this well-defined, population-based cohort is slightly lower than in previously published studies from Scandinavia. The need for orthopedic surgery and the presence of uveitis are diminished compared to studies with patients diagnosed more than 20 years ago. Children with JIA however still experience disease activity more than 50% of the time. In conclusion, we still have long-term challenges in the care for children with JIA, in spite of state-of-the-art treatment.
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29.
  • Bian, Li, et al. (författare)
  • Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice
  • 2009
  • Ingår i: ARTHRITIS RESEARCH and THERAPY. - : BioMed Central. - 1478-6354 .- 1478-6362. ; 11:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Dichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders. It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. The proapoptotic and anti-proliferative properties of DCA prompted us to investigate the effects of this compound in arthritis. Methods In the present study, we used DCA to treat murine collagen type II (CII)-induced arthritis (CIA), an experimental model of rheumatoid arthritis. DBA/1 mice were treated with DCA given in drinking water. Results Mice treated with DCA displayed much slower onset of CIA and significantly lower severity (P less than 0.0001) and much lower frequency (36% in DCA group vs. 86% in control group) of arthritis. Also, cartilage and joint destruction was significantly decreased following DCA treatment (P = 0.005). Moreover, DCA prevented arthritis-induced cortical bone mineral loss. This clinical picture was also reflected by lower levels of anti-CII antibodies in DCA-treated versus control mice, indicating that DCA affected the humoral response. In contrast, DCA had no effect on T cell-or granulocyte-mediated responses. The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls (day 30, 38.7% of ovarectomized mice had arthritis vs. only 3.4% in sham-operated group). Conclusion Our results indicate that DCA delays the onset and alleviates the progression of CIA in an estrogen-dependent manner.
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30.
  • Bilberg, Annelie, 1965, et al. (författare)
  • Significantly impaired shoulder function in the first years of rheumatoid arthritis: a controlled study
  • 2015
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Patients with rheumatoid arthritis (RA) risk impaired shoulder function due to the inflammatory process. The knowledge of shoulder function in the early years of the disease is limited. The aim was to compare shoulder function and activity limitation related to the shoulder-arm-hand in women with RA in early disease course compared to age-matched healthy women. Method: This controlled cross-sectional study included 103 women with rheumatoid arthritis and a reference group of 103 age-matched healthy women. The mean age was 47.1 (SD 10.0) years, the mean disease duration was 20.3 (SD 8.5) months and the mean DAS28 score was 3.8 (SD 1.4) among the patients. Participants were provided with self-reported questionnaires quantifying activity limitations. Shoulder function was assessed by isometric strength of the shoulder, shoulder-arm movement and shoulder pain. Hand-grip force was assessed and examination was made of tender and swollen joints among the patients. Results: Patients showed significantly (p < 0.0001) impaired shoulder muscle strength, shoulder-arm movement, and shoulder pain compared to the reference group. Patients shoulder muscle strength was approximately 65 % of the results observed in the reference group. Activity limitations related to the shoulder-arm-hand (DASH) were significantly (p < 0.0001) higher in the patient group compared to the reference group and indicates limitations in daily activities for the patients. Conclusion: Patients with RA were found to have significantly impaired shoulder function already 1.5 years after disease onset compared to age-matched subjects. Reduced shoulder muscle strength was found to be associated with activity limitations (DASH) implying that screening of the shoulder function, emphasising the shoulder muscle strength, should be initiated from disease onset.
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31.
  • Bjersing, Jan, 1966, et al. (författare)
  • Exercise and obesity in fibromyalgia: beneficial roles of IGF-1 and resistin?
  • 2013
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract Introduction: Severe fatigue is a major health problem in fibromyalgia (FM). Obesity is common in FM, but the influence of adipokines and growth factors is not clear. The aim was to examine effects of exercise on fatigue, in lean, overweight and obese FM patients. Methods: In a longitudinal study, 48 FM patients (median 52 years) exercised for 15 weeks. Nine patients were lean (body mass index, BMI 18.5 to 24.9), 26 overweight (BMI 25 to 29.9) and 13 obese. Fatigue was rated on a 0 to 100 mm scale (fibromyalgia impact questionnaire [FIQ] fatigue) and multidimensional fatigue inventory (MFI-20) general fatigue (MFIGF). Higher levels in FIQ fatigue and MFIGF indicate greater degree of fatigue. Free and total IGF-1, neuropeptides, adipokines were determined in serum and cerebrospinal fluid (CSF). Results: Baseline FIQ fatigue correlated negatively with serum leptin (r = -0.345; P = 0.016) and nerve growth factor (NGF; r = -0.412; P = 0.037). In lean patients, baseline MFIGF associated negatively with serum resistin (r = -0.694; P = 0.038). FIQ Fatigue associated negatively with CSF resistin (r = -0.365; P = 0.073). Similarly, FIQ fatigue (r = -0.444; P = 0.026) and MFIGF correlated negatively with CSF adiponectin (r = -0.508; P = 0.01). In lean patients, FIQ fatigue (P = 0.046) decreased after 15 weeks. After 30 weeks, MFIGF decreased significantly in lean (MFIGF: P = 0.017), overweight (MFIGF: P = 0.001), and obese patients (MFIGF: P = 0.016). After 15 weeks, total IGF-1 increased in lean ( P = 0.043) patients. Δ Total IGF-1 differed significantly between lean and obese patients ( P =0.010). Δ Total IGF-1 related negatively with Δ MFIGF after 15 weeks (r = -0.329; P = 0.050). After 30 weeks, Δ FIQ fatigue negatively correlated with Δ NGF (r = -0.463; P = 0.034) and positively with Δ neuropeptide Y (NPY) (r = 0.469; P = 0.032). Resistin increased after 30 weeks ( P = 0.034). Δ MFIGF correlated negatively with Δ resistin (r = -0.346; P = 0.031), being strongest in obese patients (r = -0.815; P = 0.007). In obese patients, Δ FIQ fatigue after 30 weeks correlated negatively with Δ free IGF-1 (r = -0.711; P =0.032). Conclusions: Exercise reduced fatigue in all FM patients, this effect was achieved earlier in lean patients. Baseline levels of resistin in both serum and CSF associated negatively with fatigue. Resistin was increased after the exercise period which correlated with decreased fatigue. Changes in IGF-1 indicate similar long-term effects in obese patients. This study shows reduced fatigue after moderate exercise in FM and indicates the involvement of IGF-1 and resistin in these beneficial effects. Trial registration: ClinicalTrials.gov: NCT00643006
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32.
  • Black, Rebecca Mae, et al. (författare)
  • Tissue catabolism and donor-specific dexamethasone response in a human osteochondral model of post-traumatic osteoarthritis
  • 2022
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Post-traumatic osteoarthritis (PTOA) does not currently have clinical prognostic biomarkers or disease-modifying drugs, though promising candidates such as dexamethasone (Dex) exist. Many challenges in studying and treating this disease stem from tissue interactions that complicate understanding of drug effects. We present an ex vivo human osteochondral model of PTOA to investigate disease effects on cartilage and bone homeostasis and discover biomarkers for disease progression and drug efficacy. Methods: Human osteochondral explants were harvested from normal (Collins grade 0–1) ankle talocrural joints of human donors (2 female, 5 male, ages 23–70). After pre-equilibration, osteochondral explants were treated with a single-impact mechanical injury and TNF-α, IL-6, and sIL-6R ± 100 nM Dex for 21 days and media collected every 2–3 days. Chondrocyte viability, tissue DNA content, and glycosaminoglycan (sGAG) percent loss to the media were assayed and compared to untreated controls using a linear mixed effects model. Mass spectrometry analysis was performed for both cartilage tissue and pooled culture medium, and the statistical significance of protein abundance changes was determined with the R package limma and empirical Bayes statistics. Partial least squares regression analyses of sGAG loss and Dex attenuation of sGAG loss against proteomic data were performed. Results: Injury and cytokine treatment caused an increase in the release of matrix components, proteases, pro-inflammatory factors, and intracellular proteins, while tissue lost intracellular metabolic proteins, which was mitigated with the addition of Dex. Dex maintained chondrocyte viability and reduced sGAG loss caused by injury and cytokine treatment by 2/3 overall, with donor-specific differences in the sGAG attenuation effect. Biomarkers of bone metabolism had mixed effects, and collagen II synthesis was suppressed with both disease and Dex treatment by 2- to 5-fold. Semitryptic peptides associated with increased sGAG loss were identified. Pro-inflammatory humoral proteins and apolipoproteins were associated with lower Dex responses. Conclusions: Catabolic effects on cartilage tissue caused by injury and cytokine treatment were reduced with the addition of Dex in this osteochondral PTOA model. This study presents potential peptide biomarkers of early PTOA progression and Dex efficacy that can help identify and treat patients at risk of PTOA.
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33.
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34.
  • Boeters, Debbie M., et al. (författare)
  • The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical
  • 2017
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19:1, s. 1-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored. Methods: The 1987 criteria-positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umeå and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC. Results: From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset. Conclusions: Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice.
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35.
  • Bokarewa, Maria, 1963, et al. (författare)
  • Expression and functional properties of antibodies to tissue inhibitors of metalloproteinases (TIMPs) in rheumatoid arthritis
  • 2005
  • Ingår i: Arthritis Res Ther. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Tissue inhibitors of matrix metalloproteinases (TIMPs) regulate the breakdown of extracellular matrix components and play an important role in tissue remodelling and growth, in both physiological and pathological conditions. We studied the autoimmune response to TIMPs in patients with rheumatoid arthritis (RA). Eighty-nine paired blood and synovial fluid samples from patients with RA were assessed for their reactivity with recombinant tissue inhibitors of metalloproteinases (TIMPs) 1 to 4 by an ELISA and were compared with blood from 62 healthy controls and 21 synovial fluid samples from patients with degenerative joint diseases. Presence of antibodies was established as the absorbance of the sample more than 2 standard deviations above the mean of the controls. In addition, immunoglobulin G (IgG) from blood samples of RA patients possessing TIMP antibodies was isolated on protein A-sepharose and tested for the in vitro ability to neutralize TIMP-2-dependent effects on metalloproteinase 9 (MMP9). Anti-TIMP antibodies were found in 56% of RA samples but in only 5% of the controls (P < 0.005). RA patients had high frequencies of antibodies against all TIMPs except TIMP-3. TIMP-2 antibodies were most frequently found (33%), being significantly more prevalent (P = 0.024) in patients with nonerosive than erosive RA. TIMP-1 antibodies were significantly more often found in synovial fluid samples than in the matched blood samples (P < 0.025). Importantly, the IgG fraction containing TIMP antibodies down-regulated the TIMP-2 inhibitory effect, thereby supporting MMP9 activity in vitro. In the present study, we show that RA patients frequently develop autoimmune response to TIMPs that may act as a functionally significant regulator of MMP activity and thereby of joint destruction.
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36.
  • Bokarewa, Maria, 1963, et al. (författare)
  • Survivin but not Fms-like tyrosine kinase 3 ligand is up-regulated before the onset of rheumatoid arthritis: a pilot study.
  • 2014
  • Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Antibodies against citrullinated peptides (anti-CCP) and increased levels of cytokines precede the development of rheumatoid arthritis (RA) by several years. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been identified as biomarkers of RA associated with joint destruction. Our objective was to investigate the potential of survivin and Flt3L as predictors of RA in samples from patients prior to onset of symptoms.
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37.
  • Bossini-Castillo, Lara, et al. (författare)
  • KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor
  • 2012
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 14:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. Methods: The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Results: Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. Conclusions: Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.
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38.
  • Bozovic, Gracijela, et al. (författare)
  • Exocrine pancreatic function is preserved in systemic sclerosis
  • 2019
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 21
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Systemic sclerosis (SSc) has been suggested to cause exocrine pancreatic dysfunction. However, a case-control-based autopsy study failed to associate systemic sclerosis with any pancreatic histopathology. The primary objective of this study was to examine the exocrine pancreatic function in consecutive SSc patients in relation to an age- and sex-matched control group. A secondary objective was to relate exocrine pancreatic function to radiological, laboratory, and clinical SSc characteristics. Methods: One hundred twelve consecutive patients fulfilling the 2013 American Congress of Rheumatology/European League Against Rheumatism criteria for SSc and 52 control subjects were matched for sex and age. Exocrine pancreatic function was assessed by ELISA-based measurement of fecal elastase, and levels <= 200g/g were considered pathological, i.e., representing exocrine pancreatic insufficiency. Patients were characterized regarding SSc manifestations including gastrointestinal and hepatobiliary function, by use of laboratory and clinical examinations. Pancreas parenchyma characteristics were evaluated by high-resolution computer tomography (HRCT). Results: A similar proportion of subjects exhibited pathological levels of fecal elastase among SSc patients (6/112; 5.4%) and control subjects (3/52; 5.8%). Patients with fecal elastase <= 200g/g did not differ from other SSc patients with respect to laboratory and clinical characteristics, including malnutrition. SSc subjects with low levels of fecal elastase displayed significantly lower pancreas attenuation on HRCT examinations compared to the control subjects. Conclusions: In this study encompassing 112 consecutive SSc patients and 52 matched control subjects, we were unable to associate systemic sclerosis with clinically significant exocrine pancreatic dysfunction.
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39.
  • Brink, Mikael, et al. (författare)
  • Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage
  • 2015
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. Methods: A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). Results: The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P < 0.001) and also increased significantly after disease onset (P < 0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P < 0.05, all). Conclusions: The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.
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40.
  • Bäck, Jennie, et al. (författare)
  • Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus
  • 2013
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. Methods: Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. Results: Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. Conclusions: Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.
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41.
  • C Kapetanovic, Meliha, et al. (författare)
  • Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis.
  • 2014
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • An adjuvanted pandemic H1N1 influenza (pH1N1) vaccine (Pandemrix®) was reported as highly immunogenic resulting in seroconversion in 77 to 94% of adults after administration of a single dose. The aim of the study was to investigate the impact of different anti-rheumatic treatments on antibody response to pH1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA).
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42.
  • C Kapetanovic, Meliha, et al. (författare)
  • Persistence of antibody response 1.5 years after vaccination using 7-valent pneumococcal conjugate vaccine in patients with arthritis treated with different antirheumatic drugs
  • 2013
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The aim of this study was to explore the persistence of an antibody response 1.5 years after vaccination with 7-valent pneumococcal conjugate vaccine in patients with rheumatoid arthritis (RA) or spondyloarthropathy (SpA) treated with different antirheumatic drugs. Methods: Of 505 patients initially recruited, data on current antirheumatic treatment and blood samples were obtained from 398 (79%) subjects after mean (SD, range) 1.4 (0.5; 1 to 2) years. Antibody levels against pneumococcal serotypes 23F and 6B were analyzed by using enzyme-linked immunosorbent assay (ELISA). Original treatment groups were as follows: (a) RA receiving methotrexate (MTX); (b) RA taking anti-TNF monotherapy; (c) RA taking anti-TNF+MTX; (d) SpA with anti-TNF monotherapy; (e) SpA taking anti-TNF+MTX; and (f) SpA taking NSAID/analgesics. Geometric mean levels (GMLs; 95% CI) and proportion (percentage) of patients with putative protective antibody levels >= 1 mg/L for both serotypes, calculated in different treatment groups, were compared with results 4 to 6 weeks after vaccination. Patients remaining on initial treatment were included in the analysis. Possible predictors of persistence of protective antibody response were analysed by using logistic regression analysis. Results: Of 398 patients participating in the 1.5-year follow up, 302 patients (RA, 163, and SpA, 139) had unchanged medication. Compared with postvaccination levels at 1.5 years, GMLs for each serotype were significantly lower in all groups (P between 0.035 and <0.001; paired-sample t test), as were the proportions of patients with protective antibody levels for both serotypes (P < 0.001; chi(2) test). Higher prevaccination antibody levels for both serotypes 23F and 6B were associated with better persistence of protective antibodies (P < 0.001). Compared with patients with protective antibody levels at 1.5 years, those not having protective antibody levels were older, more often women, had longer disease duration and higher HAQ and DAS, and had a lower proportion of initial responders to both serotypes. Concomitant anti-TNF treatment and MTX were identified as negative predictors of the persistence of protective antibodies among RA patients (P = 0.024 and P = 0.065, respectively). Only age 65 years or older (P = 0.017) and not antirheumatic treatment was found to be a negative predictor of protective antibodies in patients with SpA. Conclusions: After initial increase, 1.5 years after pneumococcal vaccination with 7-valent conjugate vaccine, postvaccination antibody levels decreased significantly, reaching levels before vaccination in this cohort of patients with established arthritis treated with different antirheumatic drugs. MTX and anti-TNF treatment predicted low persistence of protective immunity among patients with RA. To boost antibody response, early revaccination with conjugate vaccine might be needed in patients receiving potent immunosuppressive remedies.
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43.
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44.
  • C Kapetanovic, Meliha, et al. (författare)
  • Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis
  • 2013
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA). Methods: Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post-and pre-vaccination antibody levels and a positive antibody response (posAR) was AR >= 2. Results: In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%. Conclusion: In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.
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45.
  • Cagnotto, Giovanni, et al. (författare)
  • Abatacept in rheumatoid arthritis: survival on drug, clinical outcomes, and their predictors-data from a large national quality register
  • 2020
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background There are limited data regarding efficacy of abatacept treatment for rheumatoid arthritis (RA) outside clinical trials. Quality registers have been useful for observational studies on tumor necrosis factor inhibition in clinical practice. The aim of this study was to investigate clinical efficacy and tolerability of abatacept in RA, using a national register. Methods RA patients that started abatacept between 2006 and 2017 and were included in the Swedish Rheumatology Quality register (N = 2716) were investigated. Survival on drug was estimated using Kaplan-Meier analysis. The European League Against Rheumatism (EULAR) good response and Health Assessment Questionnaire (HAQ) response (improvement of >= 0.3) rates (LUNDEX corrected for drug survival) at 6 and at 12 months were assessed. Predictors of discontinuation were investigated by Cox regression analyses, and predictors of clinical response by logistic regression. Significance-based backward stepwise selection of variables was used for the final multivariate models. Results There was a significant difference in drug survival by previous biologic disease-modifying antirheumatic drug (bDMARD) exposure (p < 0.001), with longer survival in bionaive patients. Men (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.74-0.98) and methotrexate users (HR 0.85, 95% CI 0.76-0.95) were less likely to discontinue abatacept, whereas a high pain score predicted discontinuation (HR 1.14 per standard deviation, 95% CI 1.07-1.20). The absence of previous bDMARD exposure, male sex, and a low HAQ score were independently associated with LUNDEX-corrected EULAR good response. The absence of previous bDMARD exposure also predicted LUNDEX-corrected HAQ response. Conclusions In this population-based study of RA, bDMARD naive patients and male patients were more likely to remain on abatacept with a major clinical response.
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46.
  • Carlsén, Stefan, et al. (författare)
  • Type IX collagen deficiency enhances the binding of cartilage-specific antibodies and arthritis severity
  • 2006
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 8:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Joint cartilage is attacked in both autoimmune inflammatory and osteoarthritic processes. Type IX collagen (CIX) is a protein of importance for cartilage integrity and stability. In this study we have backcrossed a transgenic disruption of the col9a1 gene, which leads to an absence of CIX, into two different inbred mouse strains, DBA/1 and B10.Q. None of the CIX-deficient mice developed observable clinical or microscopic osteoarthritis, but DBA/1 male mice had more pronounced enthesopathic arthritis, the so-called stress-induced arthritis. Both DBA/1 and B10.Q strains are susceptible to the induction of collagen-induced arthritis, and CIX deficiency in both strains led to the development of a more severe arthritis than in the controls. Induction of arthritis with monoclonal antibodies against type II collagen (CII) led to an earlier arthritis in the paws that also involved the knee joints. The antibodies used, which were specific for the J1 and the C1I epitopes of CII, initiate their arthritogenic attack by binding to cartilage. The C1I-specific antibodies bound to cartilage better in CIX-deficient mice than in wild-type animals, demonstrating that the lack of CIX in cartilage leads to an increased accessibility of structures for antibody binding and thus making the joints more vulnerable to inflammatory attack. These findings accentuate the importance of cartilage stability; cartilage disrupted as a result of genetic disorders could be more accessible and vulnerable to an autoimmune attack by pathogenic antibodies.
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47.
  • Chizzolini, C, et al. (författare)
  • Polarized subsets of human T-helper cells induce distinct patterns of chemokine production by normal and systemic sclerosis dermal fibroblasts
  • 2006
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of fibroblasts in inflammatory processes and their cross-talk with T cells is increasingly being recognized. Our aim was to explore the capacity of dermal fibroblasts to produce inflammatory chemokines potentially involved in fibrosis occurring in response to contact with polarized human T cells. Our findings indicate that the program of chemokine production by fibroblasts is differentially regulated depending on the T-helper (Th) cell subset used to activate them. Thus, Th1 and Th2 cells preferentially induced production of IFN-gamma inducible protein (IP)-10 and IL-8, respectively, whereas monocyte chemoattractant protein (MCP)-1 was equally induced by both subsets at mRNA and protein levels. Neutralization experiments indicated that membrane-associated tumour necrosis factor-alpha and IL-1 played a major role in the induction of IL-8 and MCP-1 by Th1 and Th2 cells, whereas membrane-associated lIFN-gamma (present only in Th1 cells) was responsible, at least in part, for the lower IL-8 and higher IP-10 production induced by Th1 cells. The contributions of tumour necrosis factor-alpha, IL-1 and IFN-alpha were confirmed when fibroblasts were cultured separated in a semipermeable membrane from living T cells activated by CD3 cross-linking. We observed further differences when we explored signal transduction pathway usage in fibroblasts. Pharmacological inhibition of c-Jun N-terminal kinase and nuclear factor-kappa B resulted in inhibition of IL-8 mRNA transcription induced by Th1 cells but not that by Th2 cells, whereas inhibition of MEK/ERK (mitogen-activated protein kinase of extracellular signal-regulated kinase/extracellular signal-regulated kinase) and nuclear factor-kappa B resulted in inhibition of MCP-1 mRNA induced by Th2 but not by Th1 cells. Finally, no distinct differences in chemokine production were observed when the responses to T cell contact or to prototypic Th1 and Th2 cytokines were examined in systemic sclerosis versus normal fibroblasts. These findings indicate that fibroblasts have the potential to participate in shaping the inflammatory response through the activation of flexible programs of chemokine production that depend on the Th subset eliciting their response.
  •  
48.
  • Coates, Laura C., et al. (författare)
  • Secukinumab efficacy on resolution of enthesitis in psoriatic arthritis : pooled analysis of two phase 3 studies
  • 2019
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 21:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies. METHOD: Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3-6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment. RESULTS: A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3-6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg. CONCLUSION: Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis. TRIAL REGISTRATION: FUTURE 2: ClinicalTrials.gov, NCT01752634 (date of study registration: December 19, 2012), and EudraCT, 2012-004439-22 (date of study registration: December 12, 2012) FUTURE 3: ClinicalTrials.gov, NCT01989468 (date of study registration: November 21, 2013), and EudraCT, 2013-004002-25 (date of study registration: December 17, 2013).
  •  
49.
  • Crombie, D. E., et al. (författare)
  • Destructive effects of murine arthritogenic antibodies to type II collagen on cartilage explants in vitro
  • 2005
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Certain monoclonal antibodies (mAbs) to type II collagen (CII) induce arthritis in vivo after passive transfer and have adverse effects on chondrocyte cultures and inhibit self assembly of collagen fibrils in vitro. We have examined whether such mAbs have detrimental effects on pre-existing cartilage. Bovine cartilage explants were cultured over 21 days in the presence of two arthritogenic mAbs to CII (CIIC1 or M2139), a non-arthritogenic mAb to CII (CIIF4) or a control mAb (GAD6). Penetration of cartilage by mAb was determined by immunofluorescence on frozen sections and correlated with changes to the extracellular matrix and chondrocytes by morphometric analysis of sections stained with toluidine blue. The effects of mAbs on matrix components were examined by Fourier transform infrared microspectroscopy (FTIRM). A possible role of Fc-binding was investigated using F(ab)2 from CIIC1. All three mAbs to CII penetrated the cartilage explants and CIIC1 and M2139, but not CIIF4, had adverse effects that included proteoglycan loss correlating with mAb penetration, the later development in cultures of an abnormal superficial cellular layer, and an increased proportion of empty chondrons. FTIRM showed depletion and denaturation of CII at the explant surface in the presence of CIIC1 or M2139, which paralleled proteoglycan loss. The effects of F(ab)2 were greater than those of intact CIIC1. Our results indicate that mAbs to CII can adversely affect preformed cartilage, and that the specific epitope on CII recognised by the mAb determines both arthritogenicity in vivo and adverse effects in vitro. We conclude that antibodies to CII can have pathogenic effects that are independent of inflammatory mediators or Fc-binding.
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50.
  • Dehlin, Mats, 1968, et al. (författare)
  • Association between perinatal factors and future risk for gout-a nested case-control study
  • 2022
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Increased level of urate is the strongest risk factor for gout development but since only a minority of hyperuricemics are affected by gout, other pathogenic factors must be considered. Low birth weight is associated with future morbidities causing hyperuricemia, such as diabetes and renal disease. The purpose of this study was to investigate if, and to what extent, maternal and perinatal factors, including birth weight, are associated with future risk of being diagnosed with gout. Methods A population-based retrospective nested case-control registry study based on regional and national health care registers in Sweden. All incident cases of gout born in 1973 and onward who had received >= 1 diagnosis of gout from 2000 through 2019 in the region of western Sweden were included. Up to 5 non-gout controls were matched to each case by age, sex, and county at the year of first gout diagnosis. A range of maternal, gestational, and perinatal factors were analyzed for their potential association to future gout development. This included the health of the mother, gestational length, birth weight, number of siblings, and congenital malformations. Results Maternal diabetes, any congenital malformation, and being small for gestational age were factors that significantly increased the risk for future gout development, odds ratio (95% CI) 3.1 (1.3 to 7.4) (p=0.01), 1.33 (1.04 to 1.7) (p=0.02), and 1.75 (1.3 to 2.3) (p<.0001), respectively. Conclusions In this study, maternal diabetes and being small for gestational age increased the risk for future gout development in young adults. As of today, these conditions are becoming more prevalent and may contribute to the ongoing gout epidemic. These results require both confirmation and further delineation of underlying mechanisms.
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