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  • 1. Agca, R.
    et al.
    Heslinga, S. C.
    Rollefstad, S.
    Heslinga, M.
    McInnes, B.
    Peters, M. J. L.
    Kvien, T. K.
    Dougados, M.
    Radner, H.
    Atzeni, F.
    Primdahl, J.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    van Rompay, J.
    Zabalan, C.
    Pedersen, T. R.
    Jacobsson, L.
    de Vlam, K.
    Gonzalez-Gay, M. A.
    Semb, A. G.
    Kitas, G. D.
    Smulders, Y. M.
    Szekanecz, Z.
    Sattar, N.
    Symmons, D. P. M.
    Nurmohamed, M. T.
    EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 1, 17-28 p.Article, review/survey (Refereed)
    Abstract [en]

    Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

  • 2. Agmon-Levin, Nancy
    et al.
    Damoiseaux, Jan
    Kallenberg, Cees
    Sack, Ulrich
    Witte, Torsten
    Herold, Manfred
    Bossuyt, Xavier
    Musset, Lucille
    Cervera, Ricard
    Plaza-Lopez, Aresio
    Dias, Carlos
    Sousa, Maria Jose
    Radice, Antonella
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hultgren, Olof
    Viander, Markku
    Khamashta, Munther
    Regenass, Stephan
    Coelho Andrade, Luis Eduardo
    Wiik, Allan
    Tincani, Angela
    Ronnelid, Johan
    Bloch, Donald B.
    Fritzler, Marvin J.
    Chan, Edward K. L.
    Garcia-De la Torre, I.
    Konstantinov, Konstantin N.
    Lahita, Robert
    Wilson, Merlin
    Vainio, Olli
    Fabien, Nicole
    Sinico, Renato Alberto
    Meroni, Pierluigi
    Shoenfeld, Yehuda
    International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 1, 17-23 p.Article in journal (Refereed)
    Abstract [en]

    Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

  • 3.
    Alaish, Ram
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Safety of azathioprine and 6-mercaptopurine in patients with inflammatory bowel disease naive to thiopurine treatment2017In: International journal of clinical pharmacology and therapeutics, ISSN 0946-1965, Vol. 55, no 7, 594-600 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine if 6-mercaptopurine (MP) is better tolerated than azathioprine (AZA) as the initial thiopurine treatment in patients suffering from inflammatory bowel disease (IBD). Switching patients with IBD from AZA to MP is advocated in patients intolerant to AZA. However, no study has determined if MP is more suited than AZA as a first-line treatment for patients who are naive to thiopurine treatment. Study: The tolerance of AZA and MP treatments in clinical practice was retrospectively evaluated from start to 12 months after initiating treatment in 113 patients with IBD who were all naive to thiopurines (82 patients treated with AZA and 31 patients with MP). Results: 65% of the patients treated with AZA and 61% of the patients treated with MP tolerated their treatment during 12 months (i.e., no group difference, p = 0.742). No difference in reported side effects between the two treatments was observed. The mean equivalent initial dose (0.92 vs. 0.61 mg/kg; p < 0.001) and the mean equivalent dose at 12 months (1.98 vs. 1.65 mg/kg; p = 0.014) was significantly higher in the MP group vs. the AZA group. The proportion of patients with.MCV = 7 at 12 months was numerically higher in the MP group than in the AZA group (53% vs. 31%; p = 0.090). Conclusions: In this retrospective observational study, no differences in tolerance or adherence between AZA and MP were observed in patients naive to thiopurines. However, MP treatment was at a higher equivalent thiopurine dose than AZA treatment, which tended to be associated with better treatment response.

  • 4.
    Alenius, G M
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Jonsson, S
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Jonsson, S W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ny, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Dahlqvist, Solbritt Rantapää
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Matrix metalloproteinase 9 (MMP-9) in patients with psoriatic arthritis and rheumatoid arthritis2001In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 19, no 6, 760-760 p.Article in journal (Refereed)
  • 5.
    Alenius, Gerd-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Eriksson, C
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis?2009In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 27, no 1, 120-123 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a possible systemic effect of joint inflammation in contrast to skin disease only, by measuring IL-6 and IL-2sRalpha. METHODS: Two hundred and nineteen patients (111 male / 108 female, age 50.4+/-14.5 yrs (mean+/-SD)) with psoriasis were clinically and laboratory examined. 134 patients had inflammatory joint manifestations defined as peripheral arthritis and/or axial disease, of whom 37 had measurable inflammation, defined as ESR >25 mm/h and/or CRP >15 mg/L. RESULTS: Interleukin-6 was significantly higher in patients with joint disease and measurable inflammation ((median, Q1-Q3) 4.07, 0.92-14.60), and in patients without measured inflammation (1.22, 0.70-3.46), compared to patients with skin disease only (0.70, 0.70-1.73, p<0.001 and p=0.002 respectively). The difference between the two groups of patients with inflammatory joint manifestations was significant (p=0.001). The levels of IL-6 correlated with the actual number of joints affected with arthritis (p<0.001; rs=0.248), ESR (p<0.001; rs=0.459), CRP (p<0.001; rs=0.314) and IL-2sRalpha (p=0.002; rs=0.210). The levels of IL-2sRalpha. did not differ between the 3 groups. CONCLUSION: In this study, IL-6 was significantly higher in patients with psoriasis and inflammatory joint disease with or without routine measurable inflammatory activity compared with patients having psoriasis of the skin. We found that patients with psoriasis and joint inflammation may have systemic effects that could be captured by serum measurements of IL-6. Soluble IL-2Ralpha was not a marker of inflammation in this study.

  • 6.
    Alenius, Gerd-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Husmark, Tomas
    Theander, Elke
    Larsson, Per
    Geijer, Mats
    Teleman, Annika
    Lindqvist, Ulla R. C.
    Rheumatoid Arthritis, a More Severe Disease Than Psoriatic Arthritis?: A Comparison Of Disease Activity In Patients With Psoriatic Arthritis and Rheumatoid Arthritis From The Swedish Early Psoriatic Arthritis Registry (SwePsA) and The Swedish Rheumatology Registry For Early Rheumatoid Arthritis (SRR)2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, S150-S150, Meeting Abstract: 346 p.Article in journal (Other academic)
  • 7.
    Alenius, Gerd-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jidell, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nordmark, L
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Disease manifestations and HLA antigens in psoriatic arthritis in northern Sweden2002In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 21, no 5, 357-362 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify potential markers of aggressive joint manifestations and HLA associations in patients with psoriatic arthritis (PsA) in northern Sweden. Patients with PsA were examined clinically, with laboratory tests and radiologically. The classification of the disease was based on peripheral and/or axial engagement. HLA B17, B37 and B62 were significantly increased in PsA patients. Univariate analyses suggest that the HLA antigens B37, B62 and some clinical variables were associated with disease course. However, in multivariate analyses distal interphalangeal joint affliction and polyarticular manifestations were the only variables remaining significantly associated with irreversible joint destruction or deformity. There were no significant effects of HLA antigens. In this cross-sectional study, clinical manifestations were more reliable predictors of aggressive joint damage than were specific HLA antigens. However, HLA antigens seemed to modify the expression of the joint disease rather than being involved in joint disease susceptibility.

  • 8. 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.2008In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, no 1, R15- p.Article in journal (Refereed)
    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.

  • 9. 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.2010In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 12, no 4, R153- p.Article in journal (Refereed)
    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.

  • 10. Ambrosi, Aurelie
    et al.
    Salomonsson, Stina
    Eliasson, Håkan
    Zeffer, Elisabeth
    Dzikaite, Vijole
    Bergman, Gunnar
    Fernlund, Eva
    Theander, Elke
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Öhman, Annika
    Skogh, Thomas
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Fored, Michael
    Blomqvist, Paul
    Ekbom, Anders
    Lindström, Ulla
    Melander, Mats
    Winqvist, Ola
    Gadler, Fredrik
    Jonzon, Anders
    Sonesson, Sven-Erik
    Wahren-Herlenius, Marie
    Influence of season of birth and maternal age in the development of congenital heart block in anti-Ro-SSA/La-SSB positive pregnancies2010In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 72, no 3, 265- p.Article in journal (Refereed)
  • 11. Andersen, Grethe N.
    et al.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wikberg, Jarl E. S.
    The Melanocortin System: A New and Important Actor on the Scene of Systemic Sclerosis2011In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 63, no 10, S908-S908 p.Article in journal (Refereed)
  • 12.
    Andersen, Grethe Neumann
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Caidahl, Kenneth
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Kazzam, Elsadig
    Petersson, Ann-Sofi
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular adhesion molecule 12000In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 43, no 5, 1085-1093 p.Article in journal (Refereed)
    Abstract [en]

    Objective To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease.

    Methods We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting.

    Results Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate.

    Conclusion NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.

  • 13.
    Andersen, Grethe Neumann
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kazzam, Elsadig
    Mälar Hospital, Eskilstuna, Sweden.
    Nyberg, Gunnar
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Klintland, Natalia
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Petersson, Ann-Sofi
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Caidahl, Kenneth
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Assessment of vascular function in systemic sclerosis: indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production2002In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 46, no 5, 1324-1332 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the relationship between endothelium-dependent and endothelium-independent functions and the stiffness of conduit arteries as well as levels of endothelial activation markers in patients with systemic sclerosis (SSc).

    METHODS: Endothelium-dependent (i.e., flow-mediated) and endothelium-independent (i.e., nitroglycerin-induced) dilation of the brachial artery was measured as the percentage of change from baseline (FMD% and NTG%, respectively) in 24 SSc patients and 24 age- and sex-matched healthy controls by high-resolution ultrasound imaging. The maximum increase in systolic pressure per unit of time (dP/dt(max)), as a measure of arterial wall stiffness, was assessed in the radial artery by pulse applanation tonometry. Plasma nitrate, the most important metabolite of nitric oxide, and 24-hour urinary excretion of nitrate were measured by gas chromatography mass spectrometry. Soluble E-selectin and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured by enzyme-linked immunosorbent assay.

    RESULTS: Brachial artery FMD% and NTG% did not differ between SSc patients and controls. Radial artery dP/dt(max) was significantly increased in the patients and correlated significantly with elevated levels of plasma nitrate and sVCAM-1. Twenty-four-hour urinary nitrate excretion tended to be elevated. Brachial artery NTG% was significantly inversely correlated with levels of plasma nitrate and soluble endothelial adhesion molecules.

    CONCLUSION: The ability of the brachial arteries to dilate in response to hyperemia and nitroglycerin challenge is preserved in SSc. Stiffness of the radial artery is increased, however. Endothelial activation seems to determine the extent of the brachial artery NTG% and the radial artery dP/dt(max). The data are compatible with the hypothesis that nitrate tolerance is present in the vascular smooth muscle cells of the brachial artery wall in SSc.

  • 14. Apel, Maria
    et al.
    Uebe, Steffen
    Bowes, John
    Giardina, Emiliano
    Korendowych, Eleanor
    Juneblad, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Pasutto, Francesca
    Ekici, Arif B.
    McManus, Ross
    Ho, Pauline
    Bruce, Ian N.
    Ryan, Anthony W.
    Behrens, Frank
    Boehm, Beate
    Traupe, Heiko
    Lohmann, Joerg
    Gieger, Christian
    Wichmann, Heinz-Erich
    Padyukov, Leonid
    FitzGerald, Oliver
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    McHugh, Neil J.
    Novelli, Giuseppe
    Burkhardt, Harald
    Barton, Anne
    Reis, Andre
    Hueffmeier, Ulrike
    Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground With Ankylosing Spondylitis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 5, 1224-1231 p.Article in journal (Refereed)
    Abstract [en]

    Objective Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. Methods Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. Results Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 x 108 by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.151.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 x 102; OR 1.13 [95% CI 1.001.28]), indicating a role in the skin manifestations of psoriasis. Conclusion Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cellmediated diseases.

  • 15. Askling, Johan
    et al.
    Holmqvist, Marie
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Is Rheumatoid Arthritis a Mortal Disease?2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no 8, 1509-1511 p.Article in journal (Other academic)
  • 16.
    Askling, Johan
    et al.
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    van Vollenhoven, Ronald F
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Granath, Fredrik
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Raaschou, Pauline
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Fored, C Michael
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Baecklund, Eva
    Uppsala University Hospital, Uppsala, Sweden.
    Dackhammar, Christina
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Feltelius, Nils
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Cöster, Lars
    Linköping University Hospital, Linköping, Sweden.
    Geborek, Pierre
    Lund University Hospital, Lund, Sweden.
    Jacobsson, Lennart T
    Malmö University Hospital, Malmö, Sweden.
    Lindblad, Staffan
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Saxne, Tore
    Lund University Hospital, Lund, Sweden.
    Klareskog, Lars
    Karolinska University Hospital at Solna and Karolinska Institutet, Stockholm, Sweden.
    Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor α therapies: does the risk change with the time since start of treatment?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 11, 3180-3189 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions. METHODS: By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received. RESULTS: During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed. CONCLUSION: During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

  • 17.
    Barbe, MF
    et al.
    Department of Anatomy and Cell biology, Temple University, Philadelphia, USA.
    Xin, DL
    Department of Surgery, University of Pennsylvania, USA.
    Hadrevi, Jenny
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Elliott, ME
    Department of Neurosurgery, Thomas Jefferson University, USA.
    Barr-Gillespie, A
    College of Health Professions, Pacific University, USA.
    Sickness behaviors (reduced social interaction and pain behaviors) are linked to inflammatory mechanisms in a rat model of work-related musculoskeletal disorders2016In: Proceedings of the Human Factors and Ergonomics Society Annual Meeting, ISSN 1541-9312, Vol. 60, no 1, 975-979 p.Article in journal (Refereed)
    Abstract [en]

    We sought to determine if sickness behaviors (decreased social interaction and pain) are induced in a rat model of work-related overuse and effectiveness of anti-inflammatory treatments. Rats first trained to learn a high force reaching task (15 min/week day for 6 wks), with subsets treated prophylactically with ibuprofen or anti-TNFalpha. Others performed a high repetition high force (HRHF) task for 6 or 12 weeks (2 hrs/day, 3 days/wk) untreated, or with ibuprofen, anti-TNFalpha or rest treatments beginning task week 5. Untreated HRHF rats had increased IL-1beta, IL-6 and TNFalpha in serum and brain, increased Substance P in spinal cord, decreased social interaction and increased forepaw allodynia. Secondary antiinflammatory treatments attenuated social interaction and brain changes, but not allodynia or spinal cord changes; rest provided partial attenuation. Prophylactic treatments prevented all changes. Thus, inflammatory mechanisms mediate the development of sickness behaviors induced by work-related overuse, but not maintenance of allodynia.

  • 18.
    Bengtsson, C.
    et al.
    Department of Rheumatology, Östersund Hospital, Sweden .
    Bengtsson, A. A.
    Department of Rheumatology, Institute of Clinical Sciences, Lund University Hospital, Sweden .
    Costenbader, K. H.
    Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA .
    Jönsen, A.
    2Department of Rheumatology, Institute of Clinical Sciences, Lund University Hospital, Sweden .
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sturfelt, G.
    Department of Rheumatology, Institute of Clinical Sciences, Lund University Hospital, Sweden .
    Nived, O.
    Department of Rheumatology, Institute of Clinical Sciences, Lund University Hospital, Sweden .
    Systemic lupus erythematosus and cardiac risk factors: medical record documentation and patient adherence2011In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 20, no 10, 1057-1062 p.Article in journal (Refereed)
    Abstract [en]

    This study explores patients' knowledge of cardiac risk factors (CRFs), analyses how information and advice about CRFs are documented in clinical practice, and assesses patient adherence to received instructions to decrease CRFs. Systemic lupus erythematosus (SLE) patients with >= 4 ACR criteria participated through completing a validated cardiovascular health questionnaire (CHQ). Kappa statistics were used to compare medical records with the self-reported CHQ (agreement) and to evaluate adherence. Two hundred and eleven (72%) of the known patients with SLE participated. The mean age of the patients was 55 years. More than 70% of the SLE patients considered hypertension, obesity, smoking and hypercholesterolaemia to be very important CRFs. The agreement between medical record documentation and patients' reports was moderate for hypertension, overweight and hypercholesterolaemia (kappa 0.42-0.60) but substantial for diabetes (kappa 0.66). Patients' self-reported adherence to advice they had received regarding medication was substantial to perfect (kappa 0.65-1.0). For lifestyle changes in patients with hypertension and overweight, adherence was only fair to moderate (kappa 0.13-0.47). Swedish SLE patients' awareness of traditional CRFs was good in this study. However, the agreement between patients' self-reports and medical record documentation of CRF profiles, and patients' adherence to medical advice to CRF profiles, could be improved. Lupus (2011) 20, 1057-1062.

  • 19. Bengtsson, C
    et al.
    Öhman, Marie-Louise
    Nived, O
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Cardiovascular event in Systemic Lupus Erythematosus in northern Sweden: incidence and predictors in a 7-year follow up study2012In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 21, no 4, 452-459 p.Article in journal (Refereed)
    Abstract [en]

    Introduction. An increased rate of cardiovascular disease (CVD) has been suggested in patients with systemic lupus erythematosus (SLE). The risk for myocardial infarction (MI), coronary artery disease and stroke has been reported as particularly prevalent in younger females compared with the reference population. This study was performed to analyse the standard incidence ratio (SIR) of and predictors for cardiovascular events (CVEs) in patients with SLE from northern Sweden, with a fairly homogenous population.

    Methods. In 2000 all prevalent patients with SLE (≥4 American College of Rheumatology [ACR] criteria; n = 277) from the four northern-most counties of Sweden were assessed with clinical and laboratory analyses. Seven years follow-up data concerning MI and stroke were extracted from the national registers of hospitalization and death in Sweden. The incidence ratio among the patients was compared with that for the general population from the same catchment area using data from the same register and Statistics Sweden. To identify time to event and CVE predictors, two matched controls for each patient were used and disease related variables as CVD predictors.

    Results. The SIR for a CVE was 1.27 (95% CI 0.82-1.87) and for females separately aged 40-49 years was 8.00 (95% CI 1.65-23.38). The overall SIR for MI was 2.31 (95% CI 1.34-3.7), for females overall was 1.75 (95% CI 0.84-3.22) and for females aged between 40 and 49 years was 8.7 (95% CI 1.1-31.4). The time to an event was significantly shorter among SLE patients (p < 0.001) and was predicted by hypertension adjusted for smoking and disease. High SLEDAI and anti-cardiolipin IgG antibodies predicted an event in Cox proportional hazards regression models adjusted for age and previous MI. Diabetes, smoking ever and sex did not affect the prediction models.

    Conclusion. The risk of a CVE, or MI, was eight- or nine-fold greater among middle-aged female SLE patients. Time to event was significantly shorter and CVE was associated with SLE-related factors including hypertension and age.

  • 20. Bengtsson, Christine
    et al.
    Öhman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Prediction of cardiovascular event in systemic lupus erythematosus in northern Sweden: a 7-year follow up study2010In: Scandinavian Journal of Rheumatology. Supplement, ISSN 0301-3847, Vol. 39, no Suppl.124, S28- p.Article in journal (Refereed)
  • 21. Bengtsson, Karin
    et al.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lie, Elisabeth
    Klingberg, Eva
    Dehlin, Mats
    Exarchou, Sofia
    Lindstrom, Ulf
    Askling, Johan
    Jacobsson, Lennart T. H.
    Are Ankylosing Spondylitis, Psoriatic Arthritis and Undifferentiated Spondylarthritis Associated with an Increased Risk of Cardiovascular Disease?2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, 1057Article in journal (Other academic)
  • 22. Bengtsson, Karin
    et al.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lie, Elisabeth
    Klingberg, Eva
    Dehlin, Mats
    Exarchou, Sofia
    Lindstrom, Ulf
    Askling, Johan
    Jacobsson, Lennart T. H.
    Increased Risk of Atrioventricular Block, Atrial Fibrillation and Pacemaker Implantation in Ankylosing Spondylitis, Undifferentiated Spondylarthritis and Psoriatic Arthritis Compared to the General Population2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 10, 1059Article in journal (Other academic)
  • 23. Bengtsson, Karin
    et al.
    Jacobsson, Lennart T H
    Rydberg, Barbro
    Kvist, Göran
    Torstenson, Tomas
    Dehlin, Mats
    Hilme, Elisabet
    Lindhé, Anna
    Wallerstedt, Susanna Maria
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Box 480, S-405 30, Gothenburg, Sweden..
    Comparisons between comorbid conditions and health care consumption in rheumatoid arthritis patients with or without biological disease-modifying antirheumatic drugs: a register-based study2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, no 1, 499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Symptoms and prognosis of patients with rheumatoid arthritis (RA) have improved with more intensive therapy, including the biological disease-modifying anti-rheumatic drugs (bDMARDs). Real life data concerning how comorbidities are distributed among patients treated or not treated with bDMARDs are scarce. Our objective was to investigate differences in comorbidity and health care consumption in RA patients, with and without bDMARDs.

    METHODS: This cross-sectional study was performed in the Southwestern part of Sweden. Patients, aged ≥ 18 years and diagnosed with RA in secondary health care during 2009-2010, were identified in the regional health care database. Aggregated data of comorbidity and health care consumption were retrieved between 2006 and 2010. RA patients treated with bDMARDs on 31st December 2010 were identified in the Swedish Rheumatology Quality Register (SRQ), which includes the biologics register Anti-Rheumatic Therapy in Sweden (ARTIS). Descriptive, comparative, univariate and multiple logistic regression analyses were used to identify factors associated with bDMARDs.

    RESULTS: Seven thousand seven hundred and twelve (7712) RA patients were identified (age 64.8 ± 14.9 years, women 74.3%), of whom 1137 (14.7%) were treated with bDMARDs. Overall, the most common comorbidities were infections (69.2%), hypertension (41.1%), chronic respiratory disease (15.3%), ischemic heart disease (14.0%) and malignancy (13.7%). Patients without bDMARDs were older and had more comorbidity. In the multiple logistic regression analysis, older age, cerebrovascular and chronic respiratory disease, heart failure, depression and malignancy were all associated with no present bDMARDs. Infections were associated with bDMARDs. Patients treated with bDMARDs consumed more secondary outpatient care but less visits in primary health care compared to patients without bDMARDs.

    CONCLUSIONS: Patients treated with bDMARDs versus no bDMARDs were younger and had significantly lower period prevalence for most common comorbidities, with the exception of infections. Differences in comorbidities between RA patients with or without bDMARDs should be taken into consideration when evaluating effectiveness and safety of bDMARDs in ordinary care.

  • 24.
    Berglin, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lorentzon, Ronnie
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordmark, L
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nilsson-Sojka, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Predictors of radiological progression and changes in hand bone density in early rheumatoid arthritis2003In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 42, no 2, 268-275 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify predictors for radiological and functional outcome and bone loss in the hands in early rheumatoid arthritis (RA) during the first 2 yr of disease and to study the relationship between these variables.

    METHODS: An inception cohort of consecutively recruited patients was examined at baseline and after 12 and 24 months using X-rays of hands and feet, clinical [28-joint count, Health Assessment Questionnaire (HAQ), global visual analogue scale (VAS), grip strength] and laboratory (erythrocyte sedimentation rate, C-reactive protein, markers of bone formation and resorption) measurements and dual-energy X-ray absorptiometry measurements of the hands.

    RESULTS: Joint destruction increased significantly during the study, with the Larsen score at baseline as the strongest predictor. Radiological progression and bone loss over 24 months were significantly retarded in patients responding to therapy. The effects of the shared epitope and initial high inflammatory activity on radiological progression were overridden by the therapeutic response. Radiological progression correlated significantly with bone loss. Global VAS, Larsen score and HAQ at inclusion significantly predicted change in HAQ over time.

    CONCLUSIONS: Radiological progression and bone loss were retarded by early therapeutic response. Bone loss was related to radiological progression.

  • 25.
    Berglin, Ewa H.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Does Evaluation Of Hand Bone Loss By Digital x-Ray Radiogrammetry Within The First 3 Months After Diagnosis Of Rheumatoid Arthrits Identify Patients At Risk For Radiological Progression?2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, S834-S834, Meeting Abstract: 1958 p.Article in journal (Other academic)
  • 26.
    Berglin, Ewa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Padyukov, Leonid
    Sundin, Ulf
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Van Venrooij, Walther J
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis.2004In: Arthritis Research & Therapy, ISSN 1478-6362, Vol. 6, no 4, R303-R308 p.Article in journal (Refereed)
  • 27.
    Berglin, Ewa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Comparison of the 1987 ACR and 2010 ACR/EULAR classification criteria for rheumatoid arthritis in clinical practice: a prospective cohort study2013In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 42, no 5, 362-368 p.Article in journal (Refereed)
    Abstract [en]

    Objective: To compare application of the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for diagnosing rheumatoid arthritis (RA) in clinical practice. Method: The medical records of patients with early arthritis attending the Rheumatology Department, Umea University Hospital (n = 1026) were analysed. Patients with synovitis in at least one joint, no diagnosis other than RA being better for explaining the synovitis, and duration of symptoms less than 1 year at first visit, and at least 1 year of follow-up were included consecutively. Fulfilment of the 1987 and 2010 criteria at baseline was evaluated. Sensitivity and specificity for each criterion set, where estimated by using the outcome measures: initiation of methotrexate (MTX) therapy during the first year, and a clinical diagnosis of RA at the 1-year follow-up. Radiographs of hands and feet were evaluated using the Larsen score. Results: The study included 313 patients, of whom 56% fulfilled the 1987 ACR criteria, 74% the 2010 ACR/EULAR criteria, and 53% both sets of criteria at baseline. The sensitivity/specificity for the 1987 and 2010 criteria with MTX within the first year as the outcome measure was 0.68/0.79 and 0.84/0.54, respectively, and with a diagnosis of RA at follow-up 0.72/0.83 and 0.91/0.65, respectively. Older patients (i.e. >= 60 years) more often fulfilled the 2010 criteria. Patients who fulfilled the 2010 ACR/EULAR but not the 1987 ACR criteria had a lower Larsen score at inclusion and after 2 years. Conclusions: Compared with the 1987 ACR criteria, the 2010 ACR/EULAR criteria have higher sensitivity but lower specificity, especially in patients aged >= 60 years. The 1987 ACR criteria are suggested to predict a more erosive disease.

  • 28.
    Berglin, Ewa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Comparison of the 1987 ACR and 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis in Clinical Practice2011In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 63, no 10, S117-S117 p.Article in journal (Refereed)
  • 29. Berglund, S
    et al.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Atherothrombotic events in rheumatoid arthritis are predicted by homocysteine: a six-year follow-up study2009In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 27, no 5, 822-825 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate whether homocysteine is linked to atherothrombotic (AT) events in patients with rheumatoid arthritis (RA). METHODS: Analysis of homocysteine (Hcy) levels was carried out in 235 consecutive RA patients. They were followed-up for 6.5 years or until death, with analysis of AT risk factors and the type and length of DMARD and corticosteroid treatment. The disease history before inclusion was collected. Six categories of AT events were defined. In addition, the diagnosis of the patients at follow-up was co-analyzed with the nationwide population-based Swedish Inpatient Register and Death Register to certify all events. RESULTS: The Hcy level was found to be higher in males (p<0.05) and increased with age (p<0.001). Patients with folic acid supplementation had significantly lower levels, while those on corticosteroids had higher levels. High Hcy levels predicted AT events (n=48) during a 6.5-year follow-up adjusted for age and male sex in a logistic regression analysis. CONCLUSION: In this study, RA patients on folic acid had lower Hcy levels. High Hcy levels (in addition to age, sex and diabetes) predicted AT event prospectively.

  • 30. Bokarewa, M
    et al.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Erlandsson, M
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Survivin but NOT fms-like tyrosine kinase ligand (FLT3L) is up-regulated before onset of rheumatoid arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no Suppl. 3, 193-193 p.Article in journal (Refereed)
  • 31. Bokarewa, Maria
    et al.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Erlandsson, Malin
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Survivin but not Fms-like tyrosine kinase 3 ligand is up-regulated before the onset of rheumatoid arthritis: a pilot study2014In: Arthritis Research & Therapy, ISSN 1478-6362, Vol. 16, no 1, R45- p.Article in journal (Refereed)
    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.

  • 32.
    Boman, Antonia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Prediction of Joint Destruction in Early Rheumatoid Arthritis: RANKL but not Sclerostin or Gene Polymorphisms is Related to Joint Destruction in Early Rheumatoid Arthritis2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 33.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Sclerostin Are Related to Joint Destruction in Early Rheumatoid Arthritis Unrelated to Polymorphisms of the Genes2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 10, 3101Article in journal (Other academic)
  • 34.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis2017In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 35, no 5, 1005-1012 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47-0.65) ng/mL compared with female controls 0.49 (0.4-0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings.

  • 35. Boström, Elisabeth Almer
    et al.
    d'Elia, Helena Forsblad
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Dahlgren, Ulf
    Simark-Mattsson, Charlotte
    Hasséus, Bengt
    Carlsten, Hans
    Tarkowski, Andrej
    Bokarewa, Maria
    Salivary resistin reflects local inflammation in Sjögren's syndrome.2008In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 35, no 10, 2005-11 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the role of resistin in primary Sjögren's syndrome (pSS) and its relation to local inflammation.

    METHODS: Blood and saliva were collected from 37 patients with pSS (duration of symptoms 12.6+/-1 yrs) and 32 healthy controls. Expression of resistin in salivary glands was visualized immunohistologically, and levels of resistin were detected by ELISA. Levels of resistin were evaluated at baseline and following oral dehydroepiandrosterone (DHEA) treatment (50 mg/day). The effect of DHEA treatment on the secretion of resistin was assessed in vitro in human leukocytes after challenge with insulin and lipopolysaccharide.

    RESULTS: Levels of resistin in saliva were significantly higher in patients with pSS than in controls, while circulating levels of resistin were similar in both groups. Resistin was expressed in the epithelial cells of striated ducts and in the lymphocytic foci. Resistin levels in saliva were related to the intensity of inflammation in the minor salivary glands of pSS patients. No changes of the levels of resistin in blood or saliva were observed during DHEA treatment. Exposure of naive leukocytes to DHEA in vitro induced significant expression of resistin compared to nonstimulated peripheral blood mononuclear cells (p=0.031).

    CONCLUSION: We showed that levels of resistin are upregulated locally in the salivary glands of patients with pSS; and that the levels of resistin correspond to the intensity of lymphocytic inflammation in patients with pSS. We suggest that resistin is expressed in the salivary glands of patients with pSS and may be a driving factor of local inflammation.

  • 36.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Presence of immunological markers preceding the onset of rheumatoid arthritis2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic inflammatory disease with an unknown aetiology characterized by joint destruction. Both genetic and environmental factors contribute to the disease development with HLA-DRB1* alleles and smoking identified as most important. The disease is characterized by the presence of autoantibodies, originally by rheumatoid factor (RF) and more recently by anti citrullinated protein/peptide antibodies (ACPA) and antibodies against carbamylated peptides (CarP). These autoantibodies are present, not only after the onset of disease, but also prior to the onset of symptoms. The development of RA is a gradual process lasting several years before the onset of any joint symptom, but when and if there is a temporal difference in the development both between and within the different antibody systems is currently unknown. B-cells produce the antibodies, and a subset of B-cells, i.e., B-regulatory (Breg) cells, produces interleukin-10, and thus have the ability to down-regulate pro-inflammatory cytokines. Whether the Breg cells are involved in the pathogenesis of RA is, as yet, unknown.

    The aim of this thesis was to increase knowledge of the pathophysiological processes in the development of RA through identification of factors involved. The analyses involved detection of autoantibodies to post-translationally modified peptides/proteins in addition to RF isotypes, cell surface markers on immune cells in asymptomatic individuals, who have an increased risk of developing RA. In a co-analysis of the registers of patients with RA attending the Department of Rheumatology, with the registers from population based screening programmes within the Biobank of Northern Sweden, blood samples collected from individuals prior to the onset of symptoms were identified, as were those from population control subjects. A cohort of pre-symptomatic individuals also donated samples at the time of receiving a diagnosis of RA. First-degree relatives (FDR) of patients with RA were also identified and included for analyses.

    The levels of ten different ACPAs, i.e., (fibrinogen (Fib) α563-583(573), Fibα580-600(591), Fibβ62-81a(72), Fibβ62-81b(74), Fibβ36-52, a-enolase (CEP-1), triple helical collagen type II (citC1III), filaggrin (Fil307-324), vimentin (Vim) 2-17, and Vim60-75) were measured using the ImmunoCAP ISAC system (Phadia/ThermoFischer, Uppsala, Sweden) in blood samples from individuals before the onset of symptoms and when diagnosed with RA in comparison with those in population based controls. In a subset of samples, the levels of anti-CarP antibodies were measured using ELISA coated with anti-CarP-FCS, as well as analysis of RF of IgM, IgG and IgA isotype using the EliA assay (Phadia, Uppsala, Sweden). Breg cells were analysed both with and without stimulation ex vivo along with other cell types using flow cytometry in samples from patients with RA, their first degree relatives (FDR) and healthy controls.

    In paper I it was shown that levels of ACPA were initially restricted to a few antibodies but disseminated over time to involve additional different antibodies. The levels of antibodies to CEP-1, Fibß36-52, and filaggrin were significantly increased. In paper II, anti-CarP antibodies were positive in 5-13% of the individuals negative for the various ACPA studied. The presence of anti-CarP antibodies was significantly related to radiological destruction of joints at baseline, at follow-up after 24 months and to the radiological progress between baseline and 24months. In paper III, the relationships between the frequencies of RF isotypes, the ten different ACPA, anti-CCP2 and anti-CarP antibodies before the onset of any symptoms and the presence of certain combinations of antibodies were associated with a very high risk of developing RA. In paper IV Breg cells from patients with RA are functionally impaired and FDR showed a similar pattern by responding less to stimulation ex vivo than cells from healthy controls.

    In conclusion, individuals who subsequently develop RA have an increased number and amount of ACPAs, anti-CarP antibodies and RF of IgM, IgG and IgA isotype, several years before symptom onset. Most of the different antibodies analysed remain associated with disease development after adjustments for each separate antibody. In FDRs, Breg cells were functionally altered in that they produce less IL-10 and consequently contribute to a more inflammation-prone status, as in their relatives with RA. These findings contribute to information about the development of RA as well as a given individual’s risk(s) of developing RA and its progression.

  • 37.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Bokarewa, Maria
    Erlandsson, Malin
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Survivin But Not Fms-Like Tyrosine Kinase Ligand Is Up-Regulated Before Onset Of Rheumatoid Arthritis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, S589-S589, Meeting Abstract: 1393 p.Article in journal (Other academic)
  • 38.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hansson, M
    Mathsson-Alm, L
    Wijayatunga, Priyantha
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Verheul, M.K
    Trouw, L.A
    Holmdahl, R
    Rönnelid, J.
    Klareskog, L.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides and Anti-Carbamylated Antibodies in Individuals Before the Onset of Rheumatoid Arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, 43Article in journal (Refereed)
    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.

  • 39.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hansson, Monika
    Mathsson, Linda
    Jakobsson, Per-Johan
    Holmdahl, Rikard
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rönnelid, Johan
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 4, 899-910 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the symptom onset of rheumatoid arthritis (RA) by several years. Antibodies against 10 citrullinated autoantigen-derived peptides were analysed for reactivity before onset of symptoms. METHODS: In the Medical Biobank of Northern Sweden 409 individuals were identified, of whom 386 provided 717 samples, obtained before onset of symptoms of RA (median time 7.4 (IQR 9.3) years); 1305 population based controls were also identified. Antibodies to 10 citrullinated peptides; fibrinogen (Fib) Fibα573, Fibα591, Fibß36-52, Fibß72, Fibß74, α-enolase (CEP-1), Type II Collagen citC1(III) , filaggrin, vimentin (Vim)2-17, and Vim60-75 were analysed using a microarray system. RESULTS: The antibody fluorescence intensity of Fibß36-52, Fibß74, CEP-1, citC1(III) , and filaggrin was significantly increased in pre-disease individuals compared with controls (p<0.001). The levels of the earliest detectable antibodies (Fibα591 and Vim60-75) fluctuated over time, with only a slight increase after onset of disease. Antibodies against Fibß36-52, CEP-1 and filaggrin increased gradually reaching the highest levels of all antibodies before symptom onset. A cluster of antibodies, citC1(III) , Fibα573 and Fibß74 increased only slightly before onset of symptoms but prominently after disease onset. The odds ratio for development of RA with a combination of CEP-1 and Fibß36-52 antibodies (<3.35 years pre-dating) was 38.8 (CI95%14.5-103.5) compared with having either. CONCLUSION: Development of an immune response towards citrullinated peptides is initially restricted but expands with time to induce a more specific response with increasing levels towards onset of symptoms, particularly invoving antibodies against CEP-1, Fibß36-52 and filaggrin.

  • 40.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hansson, Monika
    Ronnelid, Johan
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Antibodies against uncitrullinated peptides seem to occur prior to the antibodies to the corresponding citrullinated peptides2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 7Article in journal (Refereed)
  • 41.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    B-Regulatory-, CD19(+)CD20(+) CD24(high)CD38(high) -Cells Are Functionally Impaired In Patients With Rheumatoid Arthritis and Healthy First Degree Relatives Compared With Controls2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, S393-S394, Meeting Abstract: 917 p.Article in journal (Other academic)
  • 42.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Verheul, M. K.
    Ronnelid, J.
    Holmdahl, R.
    Toes, R. E. M.
    Klareskog, L.
    Trouw, L. A.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    The presence of anti-carbamylated protein antibodies prior to onset of symptoms of rheumatoid arthritis (RA) is associated with radiological progression in early RA2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no Suppl. 127, Meeting Abstract: PP109, 21-22 p.Article in journal (Other academic)
  • 43.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Verheul, M. K.
    Ronnelid, J.
    Toes, R. E.
    Klareskog, L.
    Trouw, L. L.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Anti-carbamylated protein antibodies precede the onset of symptoms of rheumatoid arthritis in a Swedish biobank cohort2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, 397-398 p.Article in journal (Other academic)
  • 44.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Verheul, Marije K.
    Rönnelid, Johan
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Holmdahl, Rikard
    Toes, Rene E. M.
    Klareskog, Lars
    Trouw, Leendert A.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, 25Article in journal (Refereed)
    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.

  • 45.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lejon, K
    B-regulatory cells are functionally impaired in patients with rheumatoid arthritis and in their first degree relativesArticle in journal (Other academic)
  • 46.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B Regulatory Cells are Functionally Impaired in Patients with Rheumatoid Arthritis and in Their First-Degree Relatives Compared with Controls2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, 450-450 p.Article in journal (Other academic)
  • 47. Checa, A.
    et al.
    Idborg, H.
    Zandian, A.
    Sar, D. Garcia
    Surowiec, Izabella
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svenungsson, E.
    Jakobsson, P-J
    Nilsson, P.
    Gunnarsson, I.
    Wheelock, C. E.
    Dysregulations in circulating sphingolipids associate with disease activity indices in female patients with systemic lupus erythematosus: a cross-sectional study2017In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 26, no 10, 1023-1033 p.Article in journal (Refereed)
    Abstract [en]

    Objective The objective of this study was to investigate the association of clinical and renal disease activity with circulating sphingolipids in patients with systemic lupus erythematosus.

    Methods We used liquid chromatography tandem mass spectrometry to measure the levels of 27 sphingolipids in plasma from 107 female systemic lupus erythematosus patients and 23 controls selected using a design of experiment approach. We investigated the associations between sphingolipids and two disease activity indices, the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index. Damage was scored according to the Systemic Lupus International Collaborating Clinics damage index. Renal activity was evaluated with the British Island Lupus Activity Group index. The effects of immunosuppressive treatment on sphingolipid levels were evaluated before and after treatment in 22 female systemic lupus erythematosus patients with active disease.

    Results Circulating sphingolipids from the ceramide and hexosylceramide families were increased, and sphingoid bases were decreased, in systemic lupus erythematosus patients compared to controls. The ratio of C-16:0-ceramide to sphingosine-1-phosphate was the best discriminator between patients and controls, with an area under the receiver-operating curve of 0.77. The C-16:0-ceramide to sphingosine-1-phosphate ratio was associated with ongoing disease activity according to the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index, but not with accumulated damage according to the Systemic Lupus International Collaborating Clinics Damage Index. Levels of C-16:0- and C-24:1-hexosylceramides were able to discriminate patients with current versus inactive/no renal involvement. All dysregulated sphingolipids were normalized after immunosuppressive treatment.

    Conclusion We provide evidence that sphingolipids are dysregulated in systemic lupus erythematosus and associated with disease activity. This study demonstrates the utility of simultaneously targeting multiple components of a pathway to establish disease associations.

  • 48.
    Christensson, Marta
    et al.
    Department of Clinical Immunology, Karolinska Institutet, Huddinge.
    Pettersson, Erna
    Department of Renal Medicine, Karolinska Institutet, Huddinge University.
    Eneslätt, Kjell
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Christensson, Birger
    Department of Clinical Immunology, Karolinska Institutet, Huddinge.
    Bratt, Johan
    Department of Rheumatology, Karolinska Institutet, Huddinge University.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sundqvist, Karl-Gösta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Serum sFAS levels are elevated in ANCA-positive vasculitis compared with other autoimmune diseases2002In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 22, no 4, 220-227 p.Article in journal (Refereed)
    Abstract [en]

    The role of the Fas/FasL system in ANCA-associated vasculitis is unclear. We therefore assessed levels of soluble Fas (sFas) in sera and Fas expression on mononuclear cells from patients with ANCA-positive vasculitis and compared the results with those found in other rheumatic diseases. Serum levels of sFas were determined by ELISA. The ANCA-positive vasculitis patients studied included 29 at onset, 17 in first remission while on therapy, and 12 in quiescence. For comparison, 10 patients with Sjogren’s syndrome (SS), 14 patients with systemic lupus erythematosus (SLE), 29 patients with rheumatoid arthritis (RA), 7 patients on dialysis (DP), and 26 healthy controls (HC) were studied. In addition, Fas expression in mononuclear cells was examined at the mRNA level using reverse transcriptase (RT)-PCR in 6 vasculitis patients at onset and in first remission. The expression of CD95 on the surface of leukocytes was determined by flow cytometry in 6 vasculitis patients at onset of the disease, in 6 patients in clinical remission, and in 6 HC. Expression of Fas and FasL in renal biopsy specimens was studied using immunohistochemistry. Patients with vasculitis had high sFas levels irrespective of disease phase. Both vasculitis patients and patients with RA and SLE had significantly increased sFas levels compared with healthy controls. All patient groups had sFas levels, which correlated with raised serum creatinine values. However, the sFas levels in vasculitis patients in first remission and in quiescence were increased despite a lower serum creatinine compared with onset. Some of the vasculitis patients showed an increased mRNA expression of Fas in mononuclear cells after treatment, suggesting that Fas production fluctuates with the intensity of the disease. The expression of CD95 on leukocytes was slightly decreased in vasculitis patients compared to healthy controls. No alterations of Fas and FasL expression were seen in renal biopsy specimens. These results show that ANCA-positive vasculitis patients have high sFas levels and that the levels remain elevated even in clinical remission. The findings indicate that perturbations in the Fas/Fas ligand system may play a role in the disease process in ANCA vasculitis.

  • 49. Cobb, Joanna E.
    et al.
    Plant, Darren
    Flynn, Edward
    Tadjeddine, Meriem
    Dieude, Philippe
    Cornelis, Francois
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Goulielmos, George
    Boumpas, Dimitrios T.
    Sidiropoulos, Prodromos
    Krintel, Sophine B.
    Ornbjerg, Lykke M.
    Hetland, Merete L.
    Klareskog, Lars
    Haeupl, Thomas
    Filer, Andrew
    Buckley, Christopher D.
    Raza, Karim
    Witte, Torsten
    Schmidt, Reinhold E.
    FitzGerald, Oliver
    Veale, Douglas
    Eyre, Stephen
    Worthington, Jane
    Identification of the Tyrosine-Protein Phosphatase Non-Receptor Type 2 as a Rheumatoid Arthritis Susceptibility Locus in Europeans2013In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 6, e66456- p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA.

    Methods: A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data.

    Results: Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4x10(-9)).

    Conclusions: This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.

  • 50. Cvetkovic, Jasmina Trifunovic
    et al.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lefvert, Ann Kari
    Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1 beta, and IL-lRa genes2002In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 29, no 2, 212-219 p.Article in journal (Refereed)
    Abstract [en]

    Objective. To analyze the association of genetic polymorphisms of pro-inflammatory cytokines with rheumatoid arthritis (RA) in comparison with healthy controls from Northern Sweden and the potential contribution of these genetic variants for disease severity and development of cardiovascular complications.

    Methods. Polymerase chain reaction amplification was used for analysis of TaqI restriction fragment length polymorphism (RFLP) of interleukin-1 beta (IL-1beta), variable tandem repeat polymorphism of IL-1 receptor antagonist (IL-1Ra) gene and NcoI RFLP at position -308 of tumor necrosis factor-alpha (TNF-alpha) gene, One hundred and fifty-four patients with RA, 42 men and 112 women, were consecutively recruited into the study through the Department of Rheumatology.

    Results. The allele A1 of TNF-alpha was more common in the patient group (p < 0.01 OR = 1.62). Patients having the genotype A1A2 seemed to develop more severe disease compared with patients with A1A1 genotype: they were younger at disease onset (p < 0.05), had a higher accumulated disease activity (p < 0.05) and worse functional class (p < 0.05), Patients with genotype A2A2 of IL-1beta had higher accumulated disease activity score than patients with A1A1 and A1A2 (p < 0.05). The allelic combination A1 IL-1beta/A2 IL-1Ra was less prevalent in RA patients who developed cardiovascular complications (p < 0.005 OR = 0.20).

    Conclusions. The A1 allele of TNF-alpha associates with RA. Genotypes A1A2 of TNF-alpha and A2A2 of IL-1beta are associated with more severe disease. The allelic combination A1 IL-1beta/A2 IL-1Ra is less often present in RA patients who developed cardiovascular complications.

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