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  • 1. af Klint, Erik
    et al.
    Catrina, Anca I
    Matt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Neregråd, Petra
    Lampa, Jon
    Ulfgren, Ann-Kristin
    Klareskog, Lars
    Lindblad, Staffan
    Evaluation of arthroscopy and macroscopic scoring.2009Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, nr 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 2.
    Ajeganova, Sofia
    et al.
    Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Tesfa, Daniel
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden.;Roche AB, Med Affairs, S-10074 Stockholm, Sweden..
    Hägglund, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Fadeel, Bengt
    Karolinska Inst, Inst Environm Med, Unit Mol Toxicol, S-17177 Stockholm, Sweden..
    Vedin, Inger
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Zignego, Anna Linda
    Univ Florence, Ctr Syst Manifestat Hepatitis Viruses, Dept Internal Med, I-50134 Florence, Italy..
    Palmblad, Jan
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab2017Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, artikel-id 44Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fc gamma receptor gene (FCGR) polymorphisms and B-cell-activating factor (BAFF) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases. Methods: A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of FCGR (FCGR2A 131H/R, FCGR2B 232I/T, FCGR3A 158V/F) and BAFF promoter polymorphism -871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms. Results: The FCGR3A V allele, but not other FCGR polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON (p = 0.017). FCGR3A 158V/V and presentation with LON were associated with a longer flare-free survival (p = 0.023 and p = 0.031, respectively). FCGR3A 158V/V was related to lower IgM levels (p = 0.016). Serum BAFF levels showed no relationship with LON and BAFF -871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the BAFF -871T/T allotype compared with the C/T or C/C allotypes (p = 0.096). Conclusions: The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity FCGR3A V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the BAFF -871C/T promoter polymorphism in LON occurrence is unclear.

  • 3. Almehed, Katarina
    et al.
    d'Elia, Helena Forsblad
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Bokarewa, Maria
    Carlsten, Hans
    Role of resistin as a marker of inflammation in systemic lupus erythematosus.2008Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, nr 1, s. R15-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 4. Almehed, Katarina
    et al.
    Hetényi, Szabolcs
    Ohlsson, Claes
    Carlsten, Hans
    Forsblad-d'Elia, Helena
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Prevalence and risk factors of vertebral compression fractures in female SLE patients.2010Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 12, nr 4, s. R153-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Our objective was to determine the frequency of and factors associated with prevalent vertebral compression fractures in female systemic lupus erythematosus (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 to 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 to 82) and disease duration 11 years (1 to 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 older 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 a risk factor of at least one vertebral fracture at any site whereas low BMD in total hip was associated with vertebral fracture in the lumbar spine.

    CONCLUSIONS: 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.

  • 5. Andersson, L
    et al.
    Petersen, G
    Johnson, P
    Ståhl, Fredrik
    Högskolan i Borås, Institutionen för Vårdvetenskap.
    A web tool for finding gene candidates associated with experimentally induced arthritis in rat2005Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 7, nr 3, s. R485-R492Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 6. Andersson, MK
    et al.
    Lundberg, Pernilla
    Umeå universitet, Medicinsk fakultet, Odontologi, Oral cellbiologi.
    Ohlin, A
    Perry, MJ
    Lie, Anita
    Umeå universitet, Medicinsk fakultet, Odontologi, Oral cellbiologi.
    Stark, A
    Lerner, Ulf
    Umeå universitet, Medicinsk fakultet, Odontologi, Oral cellbiologi.
    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.2007Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 9, nr 1, s. R18-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 7.
    Andersson, Sofia E. M.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Eneljung, Tove
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Tengvall, Sara
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Jirholt, Pernilla
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Stern, Anna
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Henningsson, Louise
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Liang, Bibo
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Thorarinsdottir, Katrin
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Martensson, Inga-Lill
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Gustafsson, Kenth
    UCL, Inst Child Hlth, Mol Immunol Unit, London, England..
    Gjertsson, Inger
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.

  • 8.
    Andersson, T
    et al.
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    af Klint, E
    Strobel, S
    Andersson, U
    Stark, A
    Gelinas, R
    Lundeberg, Joakim
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Klareskog, L
    Ulfgren, A K
    Differential gene expression and protein expression levels of MMP and TIMP molecules in response to glucocorticoid treatment in arthritic patients2004Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 6, s. S18-S18Artikel i tidskrift (Övrigt vetenskapligt)
  • 9. Bengtsson, Karin
    et al.
    Forsblad-d'Elia, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Box 480405 30 Gothenburg, Sweden.
    Lie, Elisabeth
    Klingberg, Eva
    Dehlin, Mats
    Exarchou, Sofia
    Lindstrom, Ulf
    Askling, Johan
    Jacobsson, Lennart T. H.
    Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events?: A prospective nationwide population-based cohort study2017Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, artikel-id 102Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 10.
    Berglin, Ewa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Padyukov, Leonid
    Sundin, Ulf
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Stenlund, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Van Venrooij, Walther J
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis2004Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 6, nr 4, s. R303-R308Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibodies against cyclic citrullinated peptide (CCP) and rheumatoid factors (RFs) have been demonstrated to predate the onset of rheumatoid arthritis (RA) by years. A nested case–control study was performed within the Northern Sweden Health and Disease study cohort to analyse the presence of shared epitope (SE) genes, defined as HLA-DRB1*0404 or DRB1*0401, and of anti-CCP antibodies and RFs in individuals who subsequently developed RA. Patients with RA were identified from among blood donors whose samples had been collected years before the onset of symptoms. Controls matched for age, sex, and date of sampling were selected randomly from the same cohort. The SE genes were identified by polymerase chain reaction sequence-specific primers. Anti-CCP2 antibodies and RFs were determined using enzyme immunoassays. Fifty-nine individuals with RA were identified as blood donors, with a median antedating time of 2.0 years (interquartile range 0.9–3.9 years) before presenting with symptoms of RA. The sensitivity for SE as a diagnostic indicator for RA was 60% and the specificity was 64%. The corresponding figures for anti-CCP antibodies were 37% and 98%, and for RFs, 17–42% and 94%, respectively. In a logistic regression analysis, SE (odds ratio [OR] = 2.35), anti-CCP antibodies (OR = 15.9), and IgA-RF (OR = 6.8) significantly predicted RA. In a combination model analysis, anti-CCP antibodies combined with SE had the highest OR (66.8, 95% confidence interval 8.3–539.4) in predicting RA, compared with anti-CCP antibodies without SE (OR = 25.01, 95% confidence interval 2.8–222.2) or SE without anti-CCP antibodies (OR = 1.9, 95% confidence interval 0.9–4.2). This study showed that the presence of anti-CCP antibodies together with SE gene carriage is associated with a very high relative risk for future development of RA.

  • 11. Bokarewa, Maria
    et al.
    Brink, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Erlandsson, Malin
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Survivin but not Fms-like tyrosine kinase 3 ligand is up-regulated before the onset of rheumatoid arthritis: a pilot study2014Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 16, nr 1, s. R45-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: 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. Methods: This study included 47 individuals sampled before onset of RA (median 2.5 years (IQR 4.5) and 155 matched controls, all were donors to the Medical Biobank of Northern Sweden, and 36 RA patients. Levels of anti-CCP, survivin and Flt3L were measured using ELISAs and 29 cytokines/chemokines by multiplex detection. Results: Levels of survivin were increased in pre-symptomatic individuals compared with controls (P = 0.003), whilst the levels of Flt3L were similar. The frequency of survivin positivity in the pre-symptomatic individuals was increased compared with the controls (36.2 vs. 14.2%, P = 0.001) and predicted disease development (odds ratio (OR) = 3.4 (95% confidence interval (CI) 1.6-7.2)). The frequency of survivin and Flt3L in RA patients was increased compared with the controls (both, P < 0.0001, OR = 12.1 (95% CI, 5.3-27.6) and OR = 11.0 (95% CI, 3.9-30.9), respectively). Anti-CCP positive pre-symptomatic individuals and patients had significantly higher levels of survivin compared with anti-CCP2 negative individuals. In pre-symptomatic individuals, survivin correlated with IL-12, IL-1 beta and IL-9 whereas Flt3L correlated to a significantly broader spectrum of cytokines in RA patients. Conclusion: Proto-oncogene survivin was increased in individuals prior to onset of symptoms of RA and was correlated to cytokines suggesting its role at pre-clinical stages of the disease.

  • 12.
    Brink, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Hansson, M
    Mathsson-Alm, L
    Wijayatunga, Priyantha
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Verheul, M.K
    Trouw, L.A
    Holmdahl, R
    Rönnelid, J.
    Klareskog, L.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides and Anti-Carbamylated Antibodies in Individuals Before the Onset of Rheumatoid Arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. 

    Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. 

    Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. 

    Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.

  • 13.
    Brink, Mikael
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Div Rheumatol, SE-90185 Umea, Sweden..
    Hansson, Monika
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Mathsson-Alm, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Thermo Fisher Sci, Uppsala, Sweden..
    Wijayatunga, Priyantha
    Umea Univ, Dept Stat, S-90187 Umea, Sweden..
    Verheul, Marije K.
    Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands..
    Trouw, Leendert A.
    Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands..
    Holmdahl, Rikard
    Karolinska Inst, Med Inflammat Res Med Biophys & Biochem, Stockholm, Sweden..
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Klareskog, Lars
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Dept Publ Hlth & Clin Med, Div Rheumatol, SE-90185 Umea, Sweden..
    Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.

  • 14. Brink, Mikael
    et al.
    Verheul, Marije K.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Berglin, Ewa
    Holmdahl, Rikard
    Toes, Rene E. M.
    Klareskog, Lars
    Trouw, Leendert A.
    Rantapaa-Dahlqvist, Solbritt
    Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, artikel-id 25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: 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.

  • 15.
    Brink, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Verheul, Marije K.
    Rönnelid, Johan
    Berglin, Ewa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Holmdahl, Rikard
    Toes, Rene E. M.
    Klareskog, Lars
    Trouw, Leendert A.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, artikel-id 25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 16.
    Bäck, Jennie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Lood, Christian
    Bengtsson, Anders A.
    Ekdahl, Kristina Nilsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus2013Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 15, nr 6, s. R206-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 17.
    Bäck, Jennie
    et al.
    Uppsala University.
    Lood, Christian
    Skåne University Hospital;Lund University.
    Bengtsson, Anders A.
    Skåne University Hospital;Lund University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus2013Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 15, nr 6, artikel-id R206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 18.
    Delgado-Vega, Angelica M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Alarcón-Riquelme, Marta E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kozyrev, Sergey V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genetic associations in type I interferon related pathways with autoimmunity2010Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 12, s. S2-Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFN alpha/beta by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFN alpha activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.

  • 19.
    D'Elia, Helena Forsblad
    et al.
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Mattsson, Lars-Ake
    Ohlsson, Claes
    Nordborg, Elisabeth
    Carlsten, Hans
    Hormone replacement therapy in rheumatoid arthritis is associated with lower serum levels of soluble IL-6 receptor and higher insulin-like growth factor 1.2003Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 5, nr 4, s. R202-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hormone replacement therapy (HRT) modulates the imbalance in bone remodeling, thereby decreasing bone loss. Sex hormones are known to influence rheumatic diseases. The aim of this study was to investigate the effects of HRT on the serum levels of hormones and cytokines regulating bone turnover in 88 postmenopausal women with active rheumatoid arthritis (RA) randomly allocated to receive HRT plus calcium and vitamin D3 or calcium and vitamin D3 alone for 2 years. An increase in estradiol (E2) correlated strongly with improvement of bone mineral density in the hip (P < 0.001) and lumbar spine (P < 0.001). Both baseline levels and changes during the study of IL-6 and erythrocyte sedimentation rate were correlated positively (P < 0.001). HRT for 2 years resulted in an increase of the bone anabolic factor, insulin-like growth factor 1 (IGF-1) (P < 0.05) and a decrease of serum levels of soluble IL-6 receptor (sIL-6R) (P < 0.05), which is known to enhance the biological activity of IL-6, an osteoclast-stimulating and proinflammatory cytokine. Baseline levels of IL-6 and IGF-1 were inversely associated (P < 0.05), and elevation of IGF-1 was connected with decrease in erythrocyte sedimentation rate (P < 0.05) after 2 years. Interestingly, increase in serum levels of E2 was associated with reduction of sIL-6R (P < 0.05) and reduction of sIL-6R was correlated with improved bone mineral density in the lumbar spine (P < 0.05). The latter association was however not significant after adjusting for the effect of E2 (P = 0.075). The influences of IGF-1 and the IL-6/sIL-6R pathways suggest possible mechanisms whereby HRT may exert beneficial effects in RA. However, to confirm this hypothesis future and larger studies are needed.

  • 20. Deminger, Anna
    et al.
    Klingberg, Eva
    Geijer, Mats
    Gothlin, Jan
    Hedberg, Martin
    Rehnberg, Eva
    Carlsten, Hans
    Jacobsson, Lennart T.
    Forsblad-d'Elia, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    A five-year prospective study of spinal radiographic progression and its predictors in men and women with ankylosing spondylitis2018Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, artikel-id 162Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Knowledge about predictors of new spinal bone formation in patients with ankylosing spondylitis (AS) is limited. AS-related spinal alterations are more common in men; however, knowledge of whether predictors differ between sexes is lacking. Our objectives were to study spinal radiographic progression in patients with AS and investigate predictors of progression overall and by sex. Methods: Swedish patients with AS, age (mean +/- SD) 50 +/- 13 years, were included in a longitudinal study. At baseline and at 5-year follow up, spinal radiographs were graded according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Predictors were assessed by questionnaires, spinal mobility tests and blood samples. Results: Of 204 patients included, 166 (81%) were re-examined and 54% were men. Men had significantly higher mean mSASSS at baseline and higher mean increase in mSASSS than women (1.9 +/- 2.8 vs. 1.2 +/- 3.3; p = 0.005) More men than women developed new syndesmophytes (30% vs. 12%; p = 0.007). Multivariate logistic regression analyses with progression >= 2 mSASSS units over 5 years or development of new syndesmophytes as the dependent variable showed that presence of baseline AS-related spinal radiographic alterations and obesity (OR 3.78, 95% CI 1.3 to 11.2) were independent predictors of spinal radiographic progression in both sexes. High C-reactive protein (CRP) was a significant predictor in men, with only a trend seen in women. Smoking predicted progression in men whereas high Bath Ankylosing Spondylitis Metrology Index (BASMI) and exposure to bisphosphonates during follow up (OR 4.78, 95% CI 1.1 to 20.1) predicted progression in women. Conclusion: This first report on sex-specific predictors of spinal radiographic progression shows that predictors may partly differ between the sexes. New predictors identified were obesity in both sexes and exposure to bisphosphonates in women. Among previously known predictors, baseline AS-related spinal radiographic alterations predicted radiographic progression in both sexes, high CRP was a predictor in men (with a trend in women) and smoking was a predictor only in men.

  • 21. Deminger, Anna
    et al.
    Klingberg, Eva
    Lorentzon, Mattias
    Geijer, Mats
    Gothlin, Jan
    Hedberg, Martin
    Rehnberg, Eva
    Carlsten, Hans
    Jacobsson, Lennart T.
    Forsblad-d'Elia, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Which measuring site in ankylosing spondylitis is best to detect bone loss and what predicts the decline: results from a 5-year prospective study2017Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, artikel-id 273Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Studies have shown increased prevalence of osteoporosis and increased risk for vertebral fractures in patients with ankylosing spondylitis (AS). Measurements of bone mineral density (BMD) in the lumbar spine anterior-posterior (AP) projection may be difficult to interpret due to the ligamentous calcifications, and the lateral projection might be a better measuring site. Our objectives were to investigate BMD changes after 5 years at different measuring sites in patients with AS and to evaluate disease-related variables and medications as predictors for BMD changes.

    Methods: In a longitudinal study, BMD in Swedish AS patients, 50 +/- 13 years old, was measured with dual-energy x-ray absorptiometry (DXA) at the hip, the lumbar spine AP and lateral projections, and the total radius at baseline and after 5 years. Patients were assessed with questionnaires, blood samples, and spinal radiographs for grading of AS-related alterations in the spine with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and assessment of vertebral fractures by the Genant score. Multiple linear regression analyses were used to investigate predictors for BMD changes.

    Results: Of 204 patients included at baseline, 168 (82%) were re-examined after 5 years (92 men and 76 women). BMD decreased significantly at the femoral neck and radius and increased significantly at the lumbar spine, both for AP and lateral projections. Mean C-reactive protein during follow-up predicted a decrease in the femoral neck BMD (change in %, beta = -0.15, p = 0.046). Use of bisphosphonates predicted an increase in BMD at all measuring sites (p < 0.001 to 0.013), except for the total radius. Use of tumor necrosis factor inhibitors (TNFi) predicted an increase in AP spinal BMD (beta = 3.15, p = 0.012).

    Conclusion: The current study (which has a long follow-up, many measuring sites, and is the first to longitudinally assess the lateral projection of the spine in AS patients) surprisingly showed that lateral projection spinal BMD increased. This study suggests that the best site to assess bone loss in AS patients is the femoral neck and that inflammation has an adverse effect, and the use of bisphosphonates and TNFi has a positive effect, on BMD in AS patients.

  • 22.
    Deminger, Anna
    et al.
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Klingberg, Eva
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lorentzon, Mattias
    Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    Geijer, Mats
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Radiology, Örebro University Hospital, Örebro, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Göthlin, Jan
    Department of Radiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Hedberg, Martin
    Section of Rheumatology, Södra Älvsborg Hospital, Borås, Sweden.
    Rehnberg, Eva
    Section of Rheumatology, Alingsås Hospital, Alingsås, Sweden.
    Carlsten, Hans
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jacobsson, Lennart T.
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Forsblad-d'Elia, Helena
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Public Health and Clinical Medicine, Rheumatology, Umeå University, Umeå, Sweden.
    Which measuring site in ankylosing spondylitis is best to detect bone loss and what predicts the decline: results from a 5-year prospective study2017Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, artikel-id 273Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Studies have shown increased prevalence of osteoporosis and increased risk for vertebral fractures in patients with ankylosing spondylitis (AS). Measurements of bone mineral density (BMD) in the lumbar spine anterior-posterior (AP) projection may be difficult to interpret due to the ligamentous calcifications, and the lateral projection might be a better measuring site. Our objectives were to investigate BMD changes after 5 years at different measuring sites in patients with AS and to evaluate disease-related variables and medications as predictors for BMD changes.

    METHODS: In a longitudinal study, BMD in Swedish AS patients, 50 ± 13 years old, was measured with dual-energy x-ray absorptiometry (DXA) at the hip, the lumbar spine AP and lateral projections, and the total radius at baseline and after 5 years. Patients were assessed with questionnaires, blood samples, and spinal radiographs for grading of AS-related alterations in the spine with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and assessment of vertebral fractures by the Genant score. Multiple linear regression analyses were used to investigate predictors for BMD changes.

    RESULTS: Of 204 patients included at baseline, 168 (82%) were re-examined after 5 years (92 men and 76 women). BMD decreased significantly at the femoral neck and radius and increased significantly at the lumbar spine, both for AP and lateral projections. Mean C-reactive protein during follow-up predicted a decrease in the femoral neck BMD (change in %, β = -0.15, p = 0.046). Use of bisphosphonates predicted an increase in BMD at all measuring sites (p < 0.001 to 0.013), except for the total radius. Use of tumor necrosis factor inhibitors (TNFi) predicted an increase in AP spinal BMD (β = 3.15, p = 0.012).

    CONCLUSION: The current study (which has a long follow-up, many measuring sites, and is the first to longitudinally assess the lateral projection of the spine in AS patients) surprisingly showed that lateral projection spinal BMD increased. This study suggests that the best site to assess bone loss in AS patients is the femoral neck and that inflammation has an adverse effect, and the use of bisphosphonates and TNFi has a positive effect, on BMD in AS patients.

  • 23. Elkan, Ann-Charlotte
    et al.
    Håkansson, Niclas
    Frostegård, Johan
    Cederholm, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Hafström, Ingiäld
    Rheumatoid cachexia is associated with dyslipidemia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study2009Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, nr 2, s. R37-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD) independent of traditional risk factors. The aim of this study was to analyze the associations between diet, body composition, lipids and atheroprotective natural antibodies against phosphorylcholine (anti-PC) in patients with RA. METHODS: A total of 80 RA patients (76% women), mean age (standard deviation (SD)) 61.4 (12) years and median disease duration of 6 years, were assessed by food frequency questionnaire (FFQ), fatty acid profile in adipose tissue and whole-body dual energy x ray absorptiometry (DXA). Rheumatoid cachexia was defined as fat free mass index below the 25th percentile and fat mass index above the 50th percentile of a reference population. Blood lipids, oxidized low-density lipoprotein (oxLDL) and anti-PC levels were determined. RESULTS: The mean body mass index for the women and men was 25.0 and 27.0, respectively. Central obesity was found in 57% of the women (waist circumference >80 cm) and in 89% of the men (waist circumference >94 cm). In all, 18% of the women and 26% of the men had rheumatoid cachexia. These patients had significantly higher total cholesterol (P < 0.033), LDL (P < 0.029), and trendwise oxLDL (P = 0.056) as well as lower anti-PC IgM (P = 0.040), higher frequency of hypertension (69%) and metabolic syndrome (25%) than those without. The patients reported a high dietary intake of saturated fat, which partly correlated with fatty acid composition in adipose tissue and significantly with disease activity. However, patients with or without cachexia did not differ with respect to dietary fat intake or intake of Mediterranean-like diet. Additionally, patients on a Mediterranean-like diet had high levels of anti-PC (P < 0.001). CONCLUSIONS: About one in five patients with low-active RA displayed rheumatoid cachexia. This condition was associated with high levels of LDL cholesterol, low levels of atheroprotective anti-PC and high frequency of hypertension, which is of interest in the context of CVD in RA. The cachexia could not be related to diet fat intake. However, patients on a Mediterranean-like diet had high anti-PC levels in spite of similar frequency of cachexia. High anti-PC levels may provide some protection against CVD.

  • 24. Engdahl, Cecilia
    et al.
    Bondt, Albert
    Harre, Ulrike
    Raufer, Jasmin
    Pfeifle, René
    Camponeschi, Alessandro
    Wuhrer, Manfred
    Seeling, Michaela
    Mårtensson, Inga-Lill
    Nimmerjahn, Falk
    Krönke, Gerhard
    Scherer, Hans U.
    Forsblad-d'Elia, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Schett, Georg
    Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women2018Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, artikel-id 84Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation.

    Methods: Postmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fc. receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme beta-galactoside a2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells.

    Results: E2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fc. receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG.

    Conclusions: E2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibodyproducing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.

  • 25.
    Ericsson, Anna
    et al.
    University of Gothenburg, Sweden.
    Palstam, Annie
    University of Gothenburg, Sweden.
    Larsson, Anette
    University of Gothenburg, Sweden.
    Lofgren, Monika
    Danderyd Hospital Stockholm, Sweden.
    Bileviciute-Ljungar, Indre
    Danderyd Hospital Stockholm, Sweden.
    Bjersing, Jan
    University of Gothenburg, Sweden.
    Gerdle, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Kosek, Eva
    Karolinska Institute, Sweden.
    Mannerkorpi, Kaisa
    University of Gothenburg, Sweden.
    Resistance exercise improves physical fatigue in women with fibromyalgia: a randomized controlled trial2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, nr 176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Fibromyalgia (FM) affects approximately 1-3 % of the general population. Fatigue limits the work ability and social life of patients with FM. A few studies of physical exercise have included measures of fatigue in FM, indicating that exercise can decrease fatigue levels. There is limited knowledge about the effects of resistance exercise on multiple dimensions of fatigue in FM. The present study is a sub-study of a multicenter randomized controlled trial in women with FM. The purpose of the present sub-study was to examine the effects of a person-centered progressive resistance exercise program on multiple dimensions of fatigue in women with FM, and to investigate predictors of the potential change in fatigue. Methods: A total of 130 women with FM (age 22-64 years) were included in this assessor-blinded randomized controlled multicenter trial examining the effects of person-centered progressive resistance exercise compared with an active control group. The intervention was performed twice a week for 15 weeks. Outcomes were five dimensions of fatigue measured with the Multidimensional Fatigue Inventory (MFI-20). Information about background was collected and the women also completed several health-related questionnaires. Multiple linear stepwise regression was used to analyze predictors of change in fatigue in the total population. Results: A higher improvement was found at the post-treatment examination for change in the resistance exercise group, as compared to change in the active control group in the MFI-20 subscale of physical fatigue (resistance group Delta -1.7, SD 4.3, controls Delta 0.0, SD 2.7, p = 0.013), with an effect size of 0.33. Sleep efficiency was the strongest predictor of change in the MFI-20 subscale general fatigue (beta = -0.54, p = 0.031, R-2 = 0.05). Participating in resistance exercise (beta = 1.90, p = 0.010) and working fewer hours per week (beta = 0.84, p = 0.005) were independent significant predictors of change in physical fatigue (R-2 = 0.14). Conclusions: Person-centered progressive resistance exercise improved physical fatigue in women with FM when compared to an active control group.

  • 26. Ericsson, Anna
    et al.
    Palstam, Annie
    Sahlgrenska Academy, University of Gothenburg.
    Larsson, Anette
    Löfgren, Monika
    Bileviciute-Ljungar, Indre
    Bjersing, Jan
    Gerdle, Björn
    Kosek, Eva
    Mannerkorpi, Kaisa
    Resistance exercise improves physical fatigue in women with fibromyalgia: a randomized controlled trial2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Fibromyalgia (FM) affects approximately 1-3 % of the general population. Fatigue limits the work ability and social life of patients with FM. A few studies of physical exercise have included measures of fatigue in FM, indicating that exercise can decrease fatigue levels. There is limited knowledge about the effects of resistance exercise on multiple dimensions of fatigue in FM. The present study is a sub-study of a multicenter randomized controlled trial in women with FM. The purpose of the present sub-study was to examine the effects of a person-centered progressive resistance exercise program on multiple dimensions of fatigue in women with FM, and to investigate predictors of the potential change in fatigue.

    METHODS: A total of 130 women with FM (age 22-64 years) were included in this assessor-blinded randomized controlled multicenter trial examining the effects of person-centered progressive resistance exercise compared with an active control group. The intervention was performed twice a week for 15 weeks. Outcomes were five dimensions of fatigue measured with the Multidimensional Fatigue Inventory (MFI-20). Information about background was collected and the women also completed several health-related questionnaires. Multiple linear stepwise regression was used to analyze predictors of change in fatigue in the total population.

    RESULTS: A higher improvement was found at the post-treatment examination for change in the resistance exercise group, as compared to change in the active control group in the MFI-20 subscale of physical fatigue (resistance group Δ -1.7, SD 4.3, controls Δ 0.0, SD 2.7, p = 0.013), with an effect size of 0.33. Sleep efficiency was the strongest predictor of change in the MFI-20 subscale general fatigue (beta = -0.54, p = 0.031, R (2) = 0.05). Participating in resistance exercise (beta = 1.90, p = 0.010) and working fewer hours per week (beta = 0.84, p = 0.005) were independent significant predictors of change in physical fatigue (R (2) = 0.14).

    CONCLUSIONS: Person-centered progressive resistance exercise improved physical fatigue in women with FM when compared to an active control group.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT01226784 . Registered 21 October 2010.

  • 27.
    Eriksson, Catharina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
    Kokkonen, Heidi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Autoantibodies predate the onset of Systemic Lupus Erythematosus in northern Sweden2011Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, nr 1, s. R30-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and those with rheumatoid arthritis, suggesting a gradual development of these diseases. To identify autoantibodies in a Northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.

    METHODS: The register of patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and with a given date for the onset of symptoms was co-analysed with the register of the Medical Biobank, Umea, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Biobank register. Antibodies against anti- Sjogren's syndrome antigen A (Ro/SSA) (60 and 52 kDa), anti- Sjogren's syndrome antigen B (La/SSB), anti-Smith antibody (Sm), ribonucleoprotein (RNP), scleroderma-70 (Scl-70), anti- histidyl-tRNA synthetase antibody (Jo-1), double-stranded DNA (dsDNA); Centromere protein B and histones were analysed using the anti-nuclear antibody test II (ANA-II) Plus Test System (Athena Multi-Lyte(R)) on a Bio-Plex Array Reader (Luminex200). ANA were analysed using indirect immunofluorescence on Human Epidermal cells-2 (HEp2-cells) at a sample dilution of 1:100.

    RESULTS: Autoantibodies against nuclear antigens were detected 5.6 (+/- 4.7; mean +/- SD) years before the onset of symptoms and 8.7 (+/- 5.6) years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratio (OR) for anti-dsDNA predicting disease was 18.13 (CI 95%; 3.58-91.84), and for ANA 11.5 (CI 95%; 4.54-28.87). Anti-Ro/SSA antibodies appeared first, 6.6 (+/- 2.5) years prior to symptom onset. The mean number of autoantibodies in pre-diseased individuals was 1.4 and after disease onset 3.1 (P< 0.0005). The time predating disease was shorter, and the number of autoantibodies greater, in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations.

    CONCLUSIONS: Autoantibodies against nuclear antigens were detected in individuals developing SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.

  • 28. Ernberg, Malin
    et al.
    Christidis, Nikolaos
    Ghafouri, Bijar
    Bileviciute-Ljungar, Indre
    Löfgren, Monika
    Larsson, Anette
    Palstam, Annie
    Sahlgrenska Academy, University of Gothenburg.
    Bjersing, Jan
    Mannerkorpi, Kaisa
    Gerdle, Björn
    Effects of 15 weeks of resistance exercise on pro-inflammatory cytokine levels in the vastus lateralis muscle of patients with fibromyalgia2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, nr 1, artikel-id 137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: This study aimed at investigating the effect of a resistance exercise intervention on the interstitial muscle levels of pro-inflammatory cytokines in fibromyalgia (FMS) and healthy controls (CON).

    METHODS: Twenty-four female patients with FMS (54 ± 8 years) and 27 female CON (54 ± 9 years) were subjected to intramuscular microdialysis of the most painful vastus lateralis muscle before and after 15 weeks of progressive resistance exercise twice per week. Baseline dialysates were sampled in the resting muscle 140 min after insertion of the microdialysis catheter. The participants then performed repetitive dynamic contractions (knee extension) for 20 min, followed by 60 min rest. Pain intensity was assessed with a 0-100 mm visual analogue scale (VAS), and fatigue was assessed with Borg's RPE throughout microdialysis. Dialysates were sampled every 20 min and analyzed with Luminex for interleukin (IL)-1β, tumor necrosis factor (TNF) alpha, IL-6, and IL-8.

    RESULTS: At both sessions and for both groups the dynamic contractions increased pain (P < 0.012) and fatigue (P < 0.001). The levels of TNF were lower in the FMS group than the CON group at both sessions (P < 0.05), but none of the other cytokines differed between the groups. IL-6 and IL-8 increased after the dynamic contractions in both groups (P < 0.010), while TNF increased only in CON (P < 0.05) and IL-1β did not change. Overall pain intensity was reduced after the 15 weeks of resistance exercise in FMS (P < 0.05), but there was no changes in fatigue or cytokine levels.

    CONCLUSION: Progressive resistance exercise for 15 weeks did not affect the interstitial levels of IL-1β, TNF, IL-6, and IL-8 in the vastus lateralis muscle of FMS patients or CON.

    TRIAL REGISTRATION: Clinicaltrials.gov NCT01226784 , registered 21 October 2010.

  • 29.
    Ernberg, Malin
    et al.
    Karolinska Institute, Sweden; SCON, Sweden.
    Christidis, Nikolaos
    Karolinska Institute, Sweden; SCON, Sweden.
    Ghafouri, Bijar
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Bileviciute-Ljungar, Indre
    Karolinska Institute, Sweden; Danderyd Hospital, Sweden.
    Löfgren, Monika
    Karolinska Institute, Sweden; Danderyd Hospital, Sweden.
    Larsson, Anette
    University of Gothenburg, Sweden; University of Gothenburg, Sweden.
    Palstam, Annie
    University of Gothenburg, Sweden.
    Bjersing, Jan
    University of Gothenburg, Sweden.
    Mannerkorpi, Kaisa
    University of Gothenburg, Sweden; University of Gothenburg, Sweden.
    Kosek, Eva
    Karolinska Institute, Sweden; Stockholm Spine Centre, Sweden.
    Gerdle, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Effects of 15 weeks of resistance exercise on pro-inflammatory cytokine levels in the vastus lateralis muscle of patients with fibromyalgia2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, nr 137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: This study aimed at investigating the effect of a resistance exercise intervention on the interstitial muscle levels of pro-inflammatory cytokines in fibromyalgia (FMS) and healthy controls (CON). Methods: Twenty-four female patients with FMS (54 +/- 8 years) and 27 female CON (54 +/- 9 years) were subjected to intramuscular microdialysis of the most painful vastus lateralis muscle before and after 15 weeks of progressive resistance exercise twice per week. Baseline dialysates were sampled in the resting muscle 140 min after insertion of the microdialysis catheter. The participants then performed repetitive dynamic contractions (knee extension) for 20 min, followed by 60 min rest. Pain intensity was assessed with a 0-100 mm visual analogue scale (VAS), and fatigue was assessed with Borgs RPE throughout microdialysis. Dialysates were sampled every 20 min and analyzed with Luminex for interleukin (IL)-1 beta, tumor necrosis factor (TNF) alpha, IL-6, and IL-8. Results: At both sessions and for both groups the dynamic contractions increased pain (P amp;lt; 0.012) and fatigue (P amp;lt; 0.001). The levels of TNF were lower in the FMS group than the CON group at both sessions (P amp;lt; 0.05), but none of the other cytokines differed between the groups. IL-6 and IL-8 increased after the dynamic contractions in both groups (P amp;lt; 0.010), while TNF increased only in CON (P amp;lt; 0.05) and IL-1 beta did not change. Overall pain intensity was reduced after the 15 weeks of resistance exercise in FMS (P amp;lt; 0.05), but there was no changes in fatigue or cytokine levels. Conclusion: Progressive resistance exercise for 15 weeks did not affect the interstitial levels of IL-1 beta, TNF, IL-6, and IL-8 in the vastus lateralis muscle of FMS patients or CON.

  • 30. Exarchou, Sofia
    et al.
    Lindström, Ulf
    Askling, Johan
    Eriksson, Jonas K
    Forsblad-d'Elia, Helena
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg.
    Neovius, Martin
    Turesson, Carl
    Kristensen, Lars Erik
    Jacobsson, Lennart Th
    The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, nr 1, artikel-id 118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Prevalence estimates of ankylosing spondylitis vary considerably, and there are few nationwide estimates. The present study aimed to describe the national prevalence of clinically diagnosed ankylosing spondylitis in Sweden, stratified according to age, sex, geographical, and socio-economic factors, and according to subgroups with ankylosing spondylitis-related clinical manifestations and pharmacological treatment.

    METHODS: All individuals diagnosed with ankylosing spondylitis according to the World Health Organization International Classification of Disease codes, between 1967 and 2009, were identified from the National Patient Register. Data regarding disease manifestations, patient demographics, level of education, pharmacological treatment, and geographical region were retrieved from the National Patient Register and other national registers.

    RESULTS: A total of 11,030 cases with an ankylosing spondylitis diagnosis (alive, living in Sweden, and 16 to 64 years old in December 2009) were identified in the National Patient Register, giving a point prevalence of 0.18% in 2009. The prevalence was higher in northern Sweden, and lower in those with a higher level of education. Men had a higher prevalence of ankylosing spondylitis (0.23% versus 0.14%, P < 0.001), a higher frequency of anterior uveitis (25.5% versus 20.0%, P < 0.001) and were more likely to receive tumor necrosis factor inhibitors than women (15.6% versus 11.8% in 2009, P < 0.001). Women were more likely than men to have peripheral arthritis (21.7% versus 15.3%, P < 0.001), psoriasis (8.0% versus 6.9%, P = 0.03), and treatment with oral corticosteroids (14.0% versus 10.4% in 2009, P < 0.001).

    CONCLUSION: This nationwide, register-based study demonstrated a prevalence of clinically diagnosed ankylosing spondylitis of 0.18%. It revealed phenotypical and treatment differences between the sexes, as well as geographical and socio-economic differences in disease prevalence.

  • 31. Fernandes-Cerqueira, Catia
    et al.
    Ossipova, Elena
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hansson, Monika
    Mathsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Catrina, Anca I.
    Sommarin, Yngve
    Klareskog, Lars
    Lundberg, Karin
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Jakobsson, Per-Johan
    Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, artikel-id 155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA). Methods: The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC (R) system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP) 2 using the CCPlus (R) ELISA kit. Results: Two peptides derived from the fibrinogen a chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen beta chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65 %, 15 %, 35 %, and 53 % of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5 % (Cit573), 6 % (Cit591), 8 % (Cit72), and 4 % (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84 % and 63 % respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency. Conclusions: Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA.

  • 32.
    Forsblad d'Elia, Helena
    et al.
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Christgau, Stephan
    Mattsson, Lars-Ake
    Saxne, Tore
    Ohlsson, Claes
    Nordborg, Elisabeth
    Carlsten, Hans
    Hormone replacement therapy, calcium and vitamin D3 versus calcium and vitamin D3 alone decreases markers of cartilage and bone metabolism in rheumatoid arthritis: a randomized controlled trial [ISRCTN46523456].2004Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 6, nr 5, s. R457-68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to evaluate the effects of hormone replacement therapy (HRT), known to prevent osteoporosis and fractures, on markers of bone and cartilage metabolism. Furthermore, we assessed whether changes in these markers corresponded to alterations in bone mineral density and radiographic joint destructions in postmenopausal women with rheumatoid arthritis. Eighty-eight women were randomized to receive HRT, calcium, and vitamin D3, or calcium and vitamin D3 alone, for 2 years. Bone turnover was studied by analyzing serum levels of C-terminal telopeptide fragments of type I collagen (CTX-I), C-terminal telopeptide of type I collagen (ICTP), bone sialoprotein, and C-terminal propeptide of type I procollagen (PICP) and cartilage turnover by urinary levels of collagen type II C-telopeptide degradation fragments (CTX-II) and cartilage oligomeric matrix protein (COMP) in serum. Treatment with HRT resulted in decrease in CTX-I (P < 0.001), ICTP (P < 0.001), PICP (P < 0.05), COMP (P < 0.01), and CTX-II (P < 0.05) at 2 years. Reductions in CTX-I, ICTP, and PICP were associated with improved bone mineral density. Of the markers tested, CTX-I reflected bone turnover most sensitively; it was reduced by 53 +/- 6% in the patients receiving HRT. Baseline ICTP (P < 0.001), CTX-II (P < 0.01), and COMP (P < 0.05) correlated with the Larsen score. We suggest that biochemical markers of bone and cartilage turnover may provide a useful tool for assessing novel treatment modalities in arthritis, concerning both joint protection and prevention of osteoporosis.

  • 33.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    New data favouring that neurotrophins are of importance in arthritis2009Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, nr 4, s. 122-Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Neurotrophins are important in inflammation. In an article in Arthritis Research & Therapy, Barthel and collaborators give new information on the existence of neurotrophin production in the synovial tissue of arthritic joints. These findings, together with other recent findings, stress that neurotrophins should be considered important factors in arthritis. This is reinforced by the facts that they are also produced by articular chondrocytes and that receptors for these are present in the synovial tissue and on chondrocytes. The importance of neurotrophins in joints should be further studied, including examinations on the efficacy of interfering with their effects in arthritis.

  • 34.
    Forslind, Kristina
    et al.
    Helsingborg, Hospital, Helsingborg and University Hospital, Lund.
    Kälvesten, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Hälsouniversitetet.
    Hafström, Ingiäld
    Karolinska University Hospital.
    Svensson, Björn
    Helsingborg, Hospital, Helsingborg and University Hospital, Lund.
    Does digital X-ray radiogrammetry have a role in identifying patients at increased risk for joint destruction in early rheumatoid arthritis?2012Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 14, nr 5, s. R219-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    The aim of this study was to investigate the role of hand bone mineral density (BMD) loss analyzed with digital X-ray radiogrammetry (DXR) in early rheumatoid arthritis (RA) as a predictor for progression of joint damage.

    Methods

    In 379 patients with early RA, baseline and one-year hand BMD was measured with DXR and the hand bone loss (HBL) was analyzed using the smallest detectable change (HBLsdc) and tertiles (HBLtertiles). Joint damage in hands and feet were scored according to the Sharp van der Heijde (SHS) method at baseline and at one, two, five and eight years. At the same time-points Disease Activity Score (DAS28) was calculated and functional disability assessed. Rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed at baseline.

    Results

    Sixty-six percent of the patients had hand BMD loss in the first year of RA determined by HBLsdc and 65% by HBLtertiles. Radiographic progression after two, five and eight years was associated with hand bone loss defined by HBLsdc. By HBLtertiles there were significant associations at all time-points except at eight years. The change in DXR at one year (ChDXR1yr) correlated significantly and inversely with the change in SHS (ChSHS) at two, five and eight years. Multivariate analysis showed that only change in SHS during the first year and the presence of anti-CCP were independent predictors of long-term progressive joint damage. If radiographic scores were not included, DXR-BMD loss was an independent predictor. Patients with great bone loss by HBLtertiles had significantly more often high disease activity after two years. However, neither bone loss by HBLsdc or HBLtertiles nor by ChDXR1yr was an independent predictor of remission after two, five and eight years.

    Conclusions

    This study confirms previous reports of an association of decrease in DXR-BMD during the first disease year with progression of radiographic joint damage over an extended period of time. This association was independent in a regression model only when radiological findings were excluded suggesting a possible predictive role of DXR-BMD in clinical practice when radiographic evaluation is not available. However, further studies are required before this can be established.

  • 35. Gustafsson, Johanna
    et al.
    Gunnarsson, Iva
    Börjesson, Ola
    Pettersson, Susanne
    Rheumatology Unit, Department of Medicine Karolinska University Hospital, Solna, Sweden.
    Möller, Sonia
    Fei, Guo-Zhong
    Elvin, Kerstin
    Simard, Julia F.
    Hansson, Lars-Olof
    Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Lundberg, Ingrid E.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Svenungsson, Elisabet
    Predictors of the first cardiovascular event in patients with systemic lupus erythematosus: a prospective cohort study2009Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, nr 6, s. R186-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION :

    Cardiovascular disease (CVD) is a major cause of premature mortality among Systemic lupus erythematosus (SLE) patients. Many studies have measured and evaluated risk factors for premature subclinical atherosclerosis, but few studies are prospective and few have evaluated risk factors for hard endpoints, i.e. clinically important cardiovascular events (CVE). We investigated the impact of traditional and lupus associated risk factors for the first ever CVE in a longitudinal cohort of SLE patients.

    METHODS :

    A total of 182 SLE patients (mean age 43.9 years) selected to be free of CVE were included. Cardiovascular and autoimmune biomarkers were measured on samples collected after overnight fasting at baseline. Clinical information was collected at baseline and at follow up. End point was the first ever CVE (ischemic heart, cerebrovascular or peripheral vascular disease or death due to CVD). Impact of baseline characteristics/biomarkers on the risk of having a first CVE was evaluated with Cox regression.

    RESULTS :

    Follow up was 99.5% after a mean time of 8.3 years. Twenty-four patients (13%) had a first CVE. In age-adjusted Cox regression, any positive antiphospholipid antibody (aPL), elevated markers of endothelial activation (von Willebrand factor (vWf), soluble vascular cellular adhesion molecule-1 (sVCAM-1)) and fibrinogen predicted CVEs. Of SLE manifestations, arthritis, pleuritis and previous venous occlusion were positively associated with future CVEs while thrombocytopenia was negatively associated. Among traditional risk factors only age and smoking were significant predictors. In a multivariable Cox regression model age, any positive aPL, vWf and absence of thrombocytopenia were all predictors of the first CVE.

    CONCLUSIONS :

    In addition to age, positive aPL, biomarkers indicating increased endothelial cell activity/damage, and absence of thrombocytopenia were independent predictors of CVEs in this prospective study. Our results indicate that activation of the endothelium and the coagulation system are important features in SLE related CVD. Furthermore, we observed that the risk of CVEs seems to differ between subgroups of SLE patients.

  • 36. Gustafsson, Johanna
    et al.
    Simard, Julia F
    Gunnarsson, Iva
    Elvin, Kerstin
    Lundberg, Ingrid E
    Hansson, Lars-Olof
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Svenungsson, Elisabet
    Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study2012Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 14, nr 2, s. R46-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION:

    Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease. Cardiovascular disease (CVD) is common and a major cause of mortality. Studies on cardiovascular morbidity are abundant, whereas mortality studies focusing on cardiovascular outcomes are scarce. The aim of this study was to investigate causes of death and baseline predictors of overall (OM), non-vascular (N-VM), and specifically cardiovascular (CVM) mortality in SLE, and to evaluate Systematic coronary risk evaluation (SCORE).

    METHODS:

    208 SLE patients were included 1995-1999 and followed up after 12 years. Clinical evaluation, CVD risk factors, and biomarkers were recorded at inclusion. Death certificates and autopsy protocols were collected. Causes of death were divided into CVM (ischemic vascular and general atherosclerotic diseases), N-VM and death due to pulmonary hypertension. Predictors of mortality were investigated using multivariable Cox regression. SCORE and standardized mortality ratio (SMR) were calculated.

    RESULTS:

    During follow-up 42 patients died at mean age of 62 years. SMR 2.4 (CI 1.7-3.0). 48% of deaths were caused by CVM. SCORE underestimated CVM but not to a significant level. Age, high cystatin C levels and established arterial disease were the strongest predictors for all- cause mortality. After adjusting for these in multivariable analyses, only smoking of traditional risk factors, high soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity C-reactive protein (hsCRP), anti-beta2 glycoprotein-1 (abeta2GP1) and any antiphospholipid antibody (aPL) among biomarkers, remained predictive of CVM.

    CONCLUSION:

    With the exception of smoking, traditional risk factors do not capture the main underlying risk factors for CVM in SLE. Rather, cystatin C levels, inflammatory and endothelial markers, and anticardiolipin antibodies (aCL) differentiate patients with favorable versus severe cardiovascular prognosis. Our results suggest that these new biomarkers are useful in evaluating the future risk of cardiovascular mortality in SLE patients.

  • 37. Hardt, Uta
    et al.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Gunnarsson, Iva
    Clancy, Robert M
    Petri, Michelle
    Buyon, Jill P
    Silverman, Gregg J
    Svenungsson, Elisabet
    Grönwall, Caroline
    Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis2018Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, artikel-id 36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties.

    METHODS: Herein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University.

    RESULTS: In two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9-3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI ≥ 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria.

    CONCLUSIONS: Elevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis.

  • 38.
    Hjorton, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Israelsson, Elisabeth
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Jinton, Lisa
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Berggren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thörn, Kristofer
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Mo, John
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. SciLifeLaboratory.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor2018Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, artikel-id 238Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. We asked how an interleukin (IL)-1 receptor-associated kinase 4 small molecule inhibitor (IRAK4i) affects RNA-IC-induced cytokine production compared with hydroxychloroquine (HCQ).

    Methods: Plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy individuals. PBMCs from SLE patients and healthy individuals were depleted of monocytes. Cells were stimulated with RNA-containing IC (RNA-IC) in the presence or absence of IRAK4i I92 or HCQ, and cytokines were measured by immunoassay or flow cytometry. Transcriptome sequencing was performed on RNA-IC-stimulated pDCs from healthy individuals to assess the effect of IRAK4i and HCQ.

    Results: In healthy individuals, RNA-IC induced interferon (IFN)-α, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-γ, macrophage inflammatory protein (MIP)1-α, and MIP1-β production in pDC and NK cell cocultures. IFN-α production was selective for pDCs, whereas both pDCs and NK cells produced TNF-α. IRAK4i reduced the pDC and NK cell-derived cytokine production by 74–95%. HCQ interfered with cytokine production in pDCs but not in NK cells. In monocyte-depleted PBMCs, IRAK4i blocked cytokine production more efficiently than HCQ. Following RNA-IC activation of pDCs, 975 differentially expressed genes were observed (false discovery rate (FDR) < 0.05), with many connected to cytokine pathways, cell regulation, and apoptosis. IRAK4i altered the expression of a larger number of RNA-IC-induced genes than did HCQ (492 versus 65 genes).

    Conclusions: The IRAK4i I92 exhibits a broader inhibitory effect than HCQ on proinflammatory pathways triggered by RNA-IC, suggesting IRAK4 inhibition as a therapeutic option in SLE.

  • 39.
    Idborg, Helena
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Zandian, Arash
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Affinity Proteomics. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sandberg, Ann-Sofi
    Sci Life Lab, Dept Oncol Pathol, Clin Prote Mass Spectrometry, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Nilsson, Bo
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Elvin, Kerstin
    Karolinska Inst, Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Unit Clin Immunol, Stockholm, Sweden..
    Truedsson, Lennart
    Lund Univ, Dept Lab Med, Sect Microbiol Immunol & Glycobiol, Lund, Sweden..
    Sohrabian, Azita
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Ronnelid, Johan
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mo, John
    AstraZeneca R&D, Patient Safety Resp Inflammat Autoimmun Infect &, Gothenburg, Sweden..
    Grosso, Giorgia
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Kvarnström, Marika
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Lehtio, Janne
    Sci Life Lab, Dept Oncol Pathol, Clin Prote Mass Spectrometry, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Affinity Proteomics. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Svenungsson, Elisabet
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Jakobsson, Per-Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden..
    Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjogren's syndrome differ in molecular signatures and treatment perspectives2019Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, artikel-id 62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundPrevious studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers.MethodsIn a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients' autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjogren's syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups.ResultsThe aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve=0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, -1 antitrypsin, neutrophils, and triglycerides).ConclusionsOur observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments.

  • 40.
    Idborg, Helena
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.
    Zandian, Arash
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Div Affin Prote, Stockholm, Sweden.
    Sandberg, Ann-Sofi
    Sci Life Lab, Dept Oncol Pathol, Clin Prote Mass Spectrometry, Stockholm, Sweden; Karolinska Inst, Stockholm, Sweden.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Elvin, Kerstin
    Karolinska Inst, Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Unit Clin Immunol, Stockholm, Sweden.
    Truedsson, Lennart
    Lund Univ, Dept Lab Med, Sect Microbiol Immunol & Glycobiol, Lund, Sweden.
    Sohrabian, Azita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Mo, John
    AstraZeneca R&D, Patient Safety Resp Inflammat Autoimmun Infect &, Gothenburg, Sweden.
    Grosso, Giorgia
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.
    Kvarnstrom, Marika
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.
    Lehtio, Janne
    Sci Life Lab, Dept Oncol Pathol, Clin Prote Mass Spectrometry, Stockholm, Sweden; Karolinska Inst, Stockholm, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Div Affin Prote, Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.
    Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjogren's syndrome differ in molecular signatures and treatment perspectives2019Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, artikel-id 62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Previous studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers.

    Methods: In a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients’ autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjögren’s syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups.

    Results: The aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve = 0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, α-1 antitrypsin, neutrophils, and triglycerides).

    Conclusions: Our observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments.

  • 41.
    Ighe, Anna
    et al.
    Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Institutet för handikappvetenskap (IHV). Linköpings universitet, Filosofiska fakulteten.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Application of the 2012 systemic lupus international collaborating clinics classification criteria to patients on a Regional Swedish systemic lupus erythematosus register2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, artikel-id 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) network presented a new set of criteria (SLICC-12) to classify systemic lupus erythematosus (SLE). The present study is the first to evaluate the performance of SLICC-12 in an adult European study population. Thus, SLICC-12 criteria were applied to confirmed SLE cases in our regional SLE register as well as to individuals with a fair suspicion of systemic autoimmune disease who were referred to rheumatology specialists at our unit.     

    Methods

    We included 243 confirmed SLE patients who met the 1982 American College of Rheumatology (ACR-82) classification criteria and/or the Fries ‘diagnostic principle’ (presence  of antinuclear antibodies on at least one occasion plus involvement of at least two defined organ systems) and 55 controls with possible systemic autoimmune disease, including the presence of any SLE-related autoantibody.     

    Results

    SLICC-12 showed a diagnostic sensitivity of 94% (95% confidence interval (CI), 0.90 to 0.96) compared with 90% (95% CI, 0.85 to 0.93) for the updated set of ACR criteria from 1997 (ACR-97), whereas ACR-82 failed to identify every fifth true SLE case. However, the disease specificity of SLICC-12 reached only 74% (95% CI, 0.60 to 0.84) and did not change much when involvement of at least two different organs was required as an indicator of systemic disease. In addition, SLICC-12 misclassified more of the controls compared to ACR-82, ACR-97 and Fries.     

    Conclusions

    Establishing a standard definition of SLE continues to challenge lupus researchers and clinicians. We confirm that SLICC-12 has advantages with regard to diagnostic sensitivity, whereas we found the diagnostic specificity to be surprisingly low. To accomplish increased sensitivity and specificity figures, a combination of criteria sets for clinical SLE studies should be considered.

  • 42.
    Innala, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Berglin, Ewa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Möller, Bozena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Ljung, Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Smedby, Torgny
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Södergren, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Magnusson, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study2014Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 16, nr 2, s. R94-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Disease activity, severity and co-morbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in early disease.

    METHODS: In this study, 950 RA patients were followed regularly from inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender/swollen joints, visual analogue scale (VAS) pain/global, disease activity score (DAS28)) and function (health assessment questionnaire (HAQ)). Disease severity, measured by radiographs of hands/feet (erosions, Larsen score), extra-articular disease, nodules and co-morbidities and treatment (disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, biologics, nonsteroidal anti-inflammatory drugs (NSAIDs)) were recorded at inclusion and after 5 years. Autoantibodies (rheumatoid factor (RF), anti-nuclear antibodies (ANA), antibodies against cyclic citrullinated peptides (ACPA)) and genetic markers (human leukocyte antibody (HLA)-shared epitope, protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analyzed at inclusion. Data were stratified as young (YORA) and late (LORA) onset RA, defined as being below/above median age (58 years) at onset.

    RESULTS: LORA was associated with lower frequency of ACPA (P <0.05) and carriage of PTPN22-T variant (P <0.01), but with greater disease activity at inclusion measured as ESR (P < 0.001), CRP (P <0.01) and accumulated disease activity (area under the curve for DAS28) at 6 (P <0.01), 12 (P <0.01) and 24 months (P <0.05), and a higher HAQ score (P <0.01) compared with YORA. At baseline and 24 months, LORA was more often associated with erosions (P <0.01 for both) and a higher Larsen score (P <0.001 for both). LORA was more often treated with corticosteroids (P <0.01), less often with methotrexate (P <0.001) and biologics (P <0.001). YORA was more often associated with early DMARD treatment (P <0.001). Multiple regression analyses supported our findings regarding impact of age on chosen treatment.

    CONCLUSION: YORA patients were more frequently ACPA-positive. LORA was more often associated with erosions, higher Larsen scores, disease activity and HAQ at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and with less DMARDs in early disease. This could have implications for development of co-morbidities.

  • 43.
    Innala, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Möller, Bozena
    Ljung, Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Magnusson, Staffan
    Smedby, Torgny
    Södergren, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Öhman, Marie-Louise
    Rantapää Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Cardiovascular events in early rheumatoid arthritis (RA) are a result of inflammatory burden and traditional risk factors: a five year prospective study2011Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, nr 4, s. R131-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first 5 years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the 5 year follow-up period and the modulatory effect of pharmacological treatment.

    Methods All patients from the four northern-most counties of Sweden with early RA are since December 1995 consecutively recruited at diagnsosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the 5-year follow-up (T5).

    Result Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% ( p<0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5%(p<0.01) whilst smoking decreased from 29.8 to 22.4 % ( p<0.001) and the BMI from 26.3 to 25.8( p<0.05) , respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (AUC DAS28), extra-articular disease, corticosteroid use, shorter duration of treatment with DMARDs and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised ESR at inclusion and AUC DAS28 at 6 months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.

    Conclusion The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

  • 44.
    Innala, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sjöberg, Clara
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Möller, Bozena
    Ljung, Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Smedby, Torgny
    Södergren, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Magnusson, Staffan
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Co-morbidity in patients with early rheumatoid arthritis - inflammation matters2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Patients with rheumatoid arthritis (RA) suffer from co-morbidities that contribute to a shortened lifespan. Inflammation is important for the development of cardiovascular disease, but little is known on its relationship with other co-morbidities. We investigated the role of inflammation for the development of new comorbidities in early RA. Methods: Since 1995, all patients with early RA in Northern Sweden are included in a prospective study on comorbidities, with a total of 950 patients being included. At the time for this study, 726 had been ill for >= 5 years. Data on co-morbidities, clinical and laboratory disease activity and pharmacological therapy were collected from patient records and further validated using a questionnaire at RA onset (T0) and after 5 years (T5). Results: Of the patients, 53.2 % of the patients had one or more co-morbidity at onset, the commonest being: hypertension (27.3 %), obstructive pulmonary disease (13.9 %), diabetes (8.0 %), hypothyroidism (6.3 %) and malignancy (5.0 %). After 5 years, 41.0 % had developed at least one new co-morbidity, the most common being: hypertension (15.1 %), malignancy (7.6 %), stroke/transient ischemic accident (5.1 %), myocardial infarction (4.3 %) and osteoporosis (3.7 %). Age at disease onset, a raised erythrocyte sedimentation rate (ESR) at inclusion, previous treatment with glucocorticoids (GC; p < 0.001 for all), extra-articular RA (Ex-RA; p < 0.01), DAS28 (area under the curve) at 24 months (p < 0.05), previous smoking at inclusion (p = 0.058) and male gender (p < 0.01) were associated with a new co-morbidity overall at T5. Treatment with biologics (p < 0.05) reduced the risk. In multiple logistic regression modelling, ESR (p = 0.036) at inclusion was associated with a new co-morbidity after 5 years, adjusted for age, sex, smoking and GC treatment. In a similar model, Ex-RA (p < 0.05) was associated with a new co-morbidity at T5. In a third model, adjusted for age and sex, a new pulmonary co-morbidity was associated with a smoking history at inclusion (p < 0.01), but not with ESR. Conclusion: There was substantial co-morbidity among early RA patients already at disease onset, with considerable new co-morbidity being added during the first five years. Measures of disease activity were associated with the occurrence of a new co-morbidity indicating that the inflammation is of importance in this context.

  • 45.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Pratesi, Federico
    Brink, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Ärlestig, Lisbeth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    D'Amato, Claudia
    Bartaloni, Debora
    Migliorini, Paola
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Anti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens. Methods: A cohort of 521 individuals sampled before symptoms of RA appeared and 272 population controls were identified from the Biobank of Northern Sweden; 241 samples from patients with early RA were also collected. ACPA were detected by ELISA on viral citrullinated peptides (VCP) derived from Epstein-Barr-virus nuclear antigen (EBNA) 1 and EBNA2 (VCP1 and VCP2) and histone-4-derived citrullinated peptides (HCP1 and HCP2). Results: In pre-symptomatic individuals vs. patients with early RA, anti-VCP1 antibodies were detected in 10.4 % vs. 36.1 %, anti-VCP2 in 17.1 % vs. 52.3 %, anti-HCP1 in 10.2 % vs. 37.3 %, and anti-HCP2 in 16.3 % vs. 48.5 %, respectively. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals vs. controls (p < 0.001) and were increased approaching symptom onset. Anti-VCP and anti-HCP appeared simultaneously (median (IQR) 5.3 (6) years before symptom onset) and in combination yielded a high-risk ratio for disease development (OR = 8.0-18.9). Anti-VCP2 and anti-HCP2 antibodies were associated with HLA-DRB1*0401 in pre-symptomatic individuals. Three peptidylarginine deiminase (PAD)I3/PADI4 single nucleotide polymorphisms (SNPs) were significantly associated with anti-HCP1. Conclusions: Anti-VCP and anti-HCP antibodies pre-date symptom onset and predict disease development, but no hierarchy of citrullinated epitopes can be identified. These results suggest that no inciting citrullinated antigen so far described is common to all patients with RA. The association between PADI3/PADI4 polymorphism and anti-HCP1 antibodies suggests a novel link between deimination and production of ACPA.

  • 46.
    Johansson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sherina, Natalia
    Kharlamova, Nastya
    Potempa, Barbara
    Larsson, Barbro
    Israelsson, Lena
    Potempa, Jan
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Lundberg, Karin
    Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, artikel-id 201Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production. Methods: A case-control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA. Results: Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean +/- SEM; 152.7 +/- 14.8 AU/ml) and in RA patients (114.4 +/- 16.9 AU/ml), compared with controls (p < 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 +/- 0.59 and 9.29 +/- 1.81 AU/ml, respectively) compared with controls (p < 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis. Conclusions: Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.

  • 47.
    Johansson, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Reumatologi.
    Ärlestig, Lisbeth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Reumatologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Reumatologi.
    PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease2006Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, nr 1, s. R19-Artikel i tidskrift (Refereegranskat)
  • 48. Jonsen, Andreas
    et al.
    Nilsson, Sara C
    Ahlqvist, Emma
    Svenungsson, Elisabet
    Gunnarsson, Iva
    Eriksson, Karin G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bengtsson, Anders
    Zickert, Agneta
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Truedsson, Lennart
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sturfelt, Gunnar
    Blom, Anna M
    Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus2011Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, s. R206-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION:

    Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS).

    METHODS:

    The exons of complement inhibitor genes: CD46 and CFH (factor H) were fully sequenced using Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and healthy controls (n = 523).

    RESULTS:

    We found non-synonymous, heterozygous mutations in CFH in 6.1% patients with nephritis in comparison to 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two non-synonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients vs 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in non-coding regions of CD46, which were previously implicated in aHUS.

    CONCLUSION:

    SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.

  • 49.
    Juneblad, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Alenius, Gerd-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Association between the PTPN22 +1858 C/T polymorphism and psoriatic arthritis2011Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, artikel-id R45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: The purpose of the present study was to investigate the frequency of the PTPN22 +1858 C/T single nucleotide polymorphism (SNP) (rs 2476601), previously shown to be associated with several autoimmune diseases, in patients with psoriatic arthritis (PsA) in comparison with population based controls.

    METHODS: A total of 291 patients (145 male/146 female, mean age (± S.D.) 52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601 (PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls.

    RESULTS: Carriage of the risk allele, PTPN22+1858T, showed a significant association with patients with PsA compared with controls (χ2 = 6.56, P = 0.010, odds ratio (OR) 1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) (5.9 ± 1.2 vs 2.8 ± 0.5; P = 0.005).

    CONCLUSIONS: In this study the +1858T allele of the PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.

  • 50. Klingberg, Eva
    et al.
    Bilberg, Annelie
    Bjorkman, Sofia
    Hedberg, Martin
    Jacobsson, Lennart
    Forsblad-d'Elia, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi. Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Carlsten, Hans
    Eliasson, Bjorn
    Larsson, Ingrid
    Weight loss improves disease activity in patients with psoriatic arthritis and obesity: an interventional study2019Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, artikel-id 17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Obesity is over-represented in patients with psoriatic arthritis (PsA) and associated with higher disease activity, poorer effect of treatment and increased cardiovascular morbidity. Studies on the effects of weight loss are however needed. This study aimed to prospectively study the effects of weight loss treatment with very low energy diet (VLED) on disease activity in patients with PsA (CASPAR criteria) and obesity (body mass index BMI ≥ 33 kg/m2).

    Methods: VLED (640 kcal/day) was taken during 12–16 weeks, depending on pre-treatment BMI. Afterwards, an energy-restricted diet was gradually reintroduced. Weight loss treatment was given within a structured framework for support and medical follow-up.

    Treatment with conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs was held constant from 3 months before, until 6 months after baseline.

    Patients were assessed with BMI, 66/68 joints count, Leeds enthesitis index, psoriasis body surface area (BSA), questionnaires and CRP at baseline, 3 and 6 months. Primary outcome was the percentage of patients reaching minimal disease activity (MDA) and secondary outcomes were reaching Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) response criteria.

    Results: Totally 41/46 patients completed the study, 63% women, median age 54 years (IQR 48–62). At baseline increased BMI was associated with higher disease activity and poorer function.

    The median weight loss was 18.7 kg (IQR 14.6–26.5) or 18.6% (IQR 14.7–26.3) of the baseline weight. A majority of the disease activity parameters improved significantly after weight loss, including 68/66 tender/swollen joints count, CRP, BSA, Leeds enthesitis index, HAQ and patient VAS for global health, pain and fatigue. A larger weight loss resulted in more improvement in a dose-response manner. The percentage of patients with MDA increased from 29 to 54%, (p = 0.002). PsARC was reached by 46.3%. The ACR 20, 50 and 70 responses were 51.2%, 34.1% and 7.3% respectively.

    Conclusions: Short-term weight loss treatment with VLED was associated with significant positive effects on disease activity in joints, entheses and skin in patients with PsA and obesity. The study supports the hypothesis of obesity as a promotor of disease activity in PsA.

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