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  • 1.
    Ambrosi, Aurelie
    et al.
    Karolinska Institute.
    Salomonsson, Stina
    Karolinska Institute.
    Eliasson, Hakan
    Karolinska Institute.
    Zeffer, Elisabeth
    Karolinska Institute.
    Dzikaite, Vijole
    Karolinska Institute.
    Bergman, Gunnar
    Karolinska Institute.
    Fernlund, Eva
    Skane University Hospital.
    Theander, Elke
    Malmo University Hospital.
    Ryberg, Annika
    Umea University Hospital.
    Ohman, Annika
    Uppsala University.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Rantapaa, Solbritt
    Umea University Hospital.
    Fored, Michael
    Karolinska Institute.
    Blomqvist, Paul
    Karolinska Institute.
    Ekbom, Anders
    Karolinska Institute.
    Lindsrtom, Ulla
    Queen Silvia Childrens Hospital.
    Melander, Mats
    Queen Silvia Childrens Hospital.
    Winqvist, Ola
    Karolinska Institute.
    Gadler, Fredrik
    Karolinska Institute.
    Jonzon, Anders
    Uppsala University.
    Sonesson, Sven-Erik
    Karolinska Institute.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    Influence of Season of Birth and Maternal Age in the Development of Congenital Heart Block in Anti-Ro-SSA/La-SSB Positive Pregnancies in SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol 72, issue 3, pp 265-2652010In: SCANDINAVIAN JOURNAL OF IMMUNOLOGY, Blackwell Publishing Ltd , 2010, Vol. 72, no 3, p. 265-265Conference paper (Refereed)
    Abstract [en]

    n/a

  • 2.
    Ambrosi, Aurelie
    et al.
    Karolinska Institute, Stockholm.
    Salomonsson, Stina
    Karolinska Institute, Stockholm.
    Eliasson, Hakan
    Karolinska Institute, Stockholm.
    Zeffer, Elisabeth
    Karolinska Institute, Stockholm.
    Dzikaite, Vijole
    Karolinska Institute, Stockholm.
    Bergman, Gunnar
    Karolinska Institute, Stockholm.
    Fernlund, Eva
    Skane University Hospital.
    Theander, Elke
    Skane University Hospital.
    Rydberg, Annika
    Umea University Hospital.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Wallberg-Jonsson, Solveig
    Umea University Hospital.
    Ohman, Annika
    Uppsala University.
    Lundstrom, Ulla
    Sahlgrens University Hospital.
    Mellander, Mats
    Sahlgrens University Hospital.
    Winqvist, Ola
    Karolinska Institute, Stockholm.
    Fored, Michael
    Karolinska Institute, Stockholm.
    Ekbom, Anders
    Karolinska Institute, Stockholm.
    Alfredsson, Lars
    Karolinska Institute, Stockholm.
    Kallberg, Henrik
    Karolinska Institute, Stockholm.
    Gadler, Fredrik
    Karolinska Institute, Stockholm.
    Jonzon, Anders
    Uppsala University.
    Sonesson, Sven-Erik
    Karolinska Institute.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    DEVELOPMENT OF HEART BLOCK IN SSA/SSB AUTOANTIBODY-POSITIVE PREGNANCIES IS ASSOCIATED WITH MATERNAL AGE AND DISPLAY A SEASON-OF-BIRTH PATTERN in ANNALS OF THE RHEUMATIC DISEASES, vol 70, issue , pp2011In: ANNALS OF THE RHEUMATIC DISEASES, BMJ Publishing Group , 2011, Vol. 70Conference paper (Refereed)
    Abstract [en]

    n/a

  • 3.
    Ambrosi, Aurelie
    et al.
    Karolinska Institutet, Stockholm.
    Salomonsson, Stina
    Karolinska Institutet, Stockholm.
    Eliasson, Håkan
    Karolinska Institutet, Stockholm.
    Zeffer, Elisabeth
    Karolinska Institutet, Stockholm.
    Skog, Amanda
    Karolinska Institutet, Stockholm.
    Dzikaite, Vijole
    Karolinska Institutet, Stockholm.
    Bergman, Gunnar
    Karolinska Institutet, Stockholm.
    Fernlund, Eva
    Skåne University Hospital, Lund.
    Tingström, Joanna
    Skåne University Hospital, Lund.
    Theander, Elke
    Skåne University Hospital, Malmö.
    Rydberg, Annika
    Umeå University Hospital.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Öhman, Annika
    Uppsala University.
    Lundström, Ulla
    Sahlgrenska University Hospital.
    Mellander, Mats
    Sahlgrenska University Hospital.
    Winqvist, Ola
    Karolinska Institutet, Stockholm.
    Fored, Michael
    Karolinska Institutet, Stockholm.
    Ekbom, Anders
    Karolinska Institutet, Stockholm.
    Alfredsson, Lars
    Institute of Environmental Medicine, Stockholm.
    Källberg, Henrik
    Institute of Environmental Medicine, Stockholm.
    Olsson, Tomas
    Karolinska Institutet, Stockholm.
    Gadler, Fredrik
    Karolinska Institutet, Stockholm.
    Jonzon, Anders
    Sahlgrenska University Hospital, Göteborg.
    Kockum, Ingrid
    Karolinska Institutet, Stockholm.
    Sonesson, Sven-Erik
    Karolinska Institutet, Stockholm.
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm.
    Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 3, p. 334-340Article in journal (Refereed)
    Abstract [en]

    Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. less thanbrgreater than less thanbrgreater thanMethods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. less thanbrgreater than less thanbrgreater thanResults There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (pandlt;0.05). Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (pandlt;0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. less thanbrgreater than less thanbrgreater thanConclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.

  • 4.
    Björk, Mathilda
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Occupational Therapy. Linköping University, Faculty of Health Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Haglund, Lena
    Linköping University, Department of Neuroscience and Locomotion, Occupational Therapy. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Hand function in women and men with early rheumatoid arthritis: A prospective study over three years (the Swedish TIRA project)2006In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 35, no 1, p. 15-19Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the course of hand function in women and men during the first 3 years after diagnosis of recent-onset rheumatoid arthritis (RA), to investigate sex differences in hand function, and to study correlations between and within hand function assessments.

    Methods: A total of 276 patients (69% women) with RA of a maximal duration of 12 months were recruited to the study. Hand function was assessed by the Grip Ability Test (GAT) and Signals of Functional Impairment (SOFI). Peak and average grip force over 10 s in the right and left hand was measured by an electronic device.

    Results: Hand function was affected at diagnosis, but had improved significantly at the 3-months' follow-up and then remained stable (but still affected) in both women and men. As assessed by SOFI, hand function was worse in men than in women, whereas women had significantly lower grip force. GAT, grip force, and SOFI correlated weakly. The average and peak values of grip force correlated strongly, as did the grip force in the right and the left hand.

    Conclusion: Hand function was profoundly affected at diagnosis of RA, but improved significantly within 3 months and remained stable (but still affected) over 3 years. As expected, women on average had significantly lower grip force than men.

  • 5.
    Björk, Mathilda
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Occupational Therapy. Linköping University, Faculty of Health Sciences. The Vårdal Foundation, The Swedish Institute for Health Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Gerdle, Björn
    Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Pain and Occupational Centre, Pain and Rehabilitation Centre.
    Hand Function and Activity Limitation According to Health Assessment Questionnaire in Patients with Rheumatoid Arthritis and Healthy Referents: 5-Year Followup of Predictors of Activity Limitation (The Swedish TIRA Project)2007In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 34, no 2, p. 296-302Article in journal (Refereed)
    Abstract [en]

    Objective: This study identifies baseline predictors of future activity limitation in rheumatoid arthritis (RA). To reinforce the utility of instruments assessing functional ability/activity limitation, we used reference data from healthy referents.

    Methods: This study includes 189 patients (69% women) with recent-onset RA (onset of joint swelling not more than 12 months at diagnosis) in a prospective cohort ("the Swedish TIRA project") during 27 months from 1996 through 1998. Regular followups were done for a period of 5 years, and 123 healthy persons (50% women) were recruited as referents. Hand function was assessed by the "grip ability test (GAT)" and "signals of functional impairment" (SOFI). Grip force was measured with the electronic device GrippitTM. Activity limitation was assessed with the Swedish version of the Health Assessment Questionnaire (HAQ).

    Results: Throughout the study and for both sexes, GAT, grip force, SOFI-hand, and HAQ were significantly different for the patients compared to healthy referents. In the healthy referents, HAQ was mainly related to age and GAT, whereas in RA HAQ was most obviously linked to grip force. Five years after diagnosis only 8% of HAQ outcome was explained by the baseline measures: HAQ, grip force, SOFI-lower limb, sex, walking speed, and GAT.

    Conclusion: Our study provides valuable reference data for several functional ability and activity limitation measures. The HAQ score was explained by different variables in healthy referents compared to patients with RA. Five years after diagnosis only 8% of HAQ outcome was explained by the variables assessed at inclusion.

  • 6.
    Cedergren, Jan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Follin, Per
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Lindmark, Maria
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Inducible nitric oxide synthase (NOS II) is constitutive in human neutrophils2003In: APMIS, ISSN 0903-4641, Vol. 111, no 10, p. 963-968Article in journal (Refereed)
    Abstract [en]

    The objective was to study the expression of inducible nitric oxide synthase (NOS II) in and NO production by human blood neutrophils and in in vivo exudated neutrophils. Cellular expression of NOS II was evaluated by flow cytometry in whole blood, in isolated blood neutrophils, and in neutrophils obtained by exudation in vivo into skin chambers. Neutrophil NOS II was also demonstrated by Western blotting. Uptake of 3H-labelled L-arginine was studied in vitro and NOS activity measured in a whole cell assay by the conversion of 3H-arginine to 3H-citrulline. In contrast to unseparated blood cells, NOS II was demonstrable both in isolated blood neutrophils and exudated cells. The failure to detect NOS II by flow cytometry in whole blood cells thus proved to be due to the quenching effect of hemoglobin. Western blotting revealed a 130 kD band corresponding to NOS II in isolated blood neutrophils, but detection was dependent on diisopropylfluorophosphate for proteinase inhibition. L-arginine was taken up by neutrophils, but enzymatic activity could not be demonstrated. We conclude that human neutrophils constitutively express NOS II, but that its demonstration by FITC-labelling is inhibited by hemoglobin-mediated quenching in whole blood samples.

  • 7.
    Cedergren, Jan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Inducible nitric oxide synthase is expressed in synovial fluid granulocytes2002In: Clinical Experimental Immunology, ISSN 0009-9104, Vol. 130, p. 150-155Article in journal (Refereed)
    Abstract [en]

    The objective of the study was to evaluate the NO-producing potential of synovial fluid (SF) cells. SF from 15 patients with arthritis was compared with blood from the same individuals and with blood from 10 healthy controls. Cellular expression of inducible nitric oxide synthase (iNOS) was analysed by flow cytometry. High-performance liquid chromatography was used to measure L-arginine and L-citrulline. Nitrite and nitrate were measured colourimetrically utilizing the Griess' reaction. Compared to whole blood granulocytes in patients with chronic arthritis, a prominent iNOS expression was observed in SF granulocytes (P < 0.001). A slight, but statistically significant, increase in iNOS expression was also recorded in lymphocytes and monocytes from SF. L-arginine was elevated in SF compared to serum (257 ± 78 versus 176 ± 65 µmol/l, P = 0.008), whereas a slight increase in L-citrulline (33 ± 11 versus 26 ± 9 µmol/l), did not reach statistical significance. Great variations but no significant differences were observed comparing serum and SF levels of nitrite and nitrate, respectively, although the sum of nitrite and nitrate tended to be elevated in SF (19.2 ± 20.7 versus 8,6 ± 6.5 µmol/l,P = 0.054). Synovial fluid leucocytes, in particular granulocytes, express iNOS and may thus contribute to intra-articular NO production in arthritis.

  • 8.
    Cedergren, Jan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients2007In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 34, no 11, p. 2162-2170Article in journal (Refereed)
    Abstract [en]

    Objective: To compare total and intracellular oxidative activation of blood and synovial fluid (SF) neutrophils from patients with rheumatoid arthritis (RA) and other arthritides with blood donor neutrophils.

    Methods: Peripheral blood and SF samples were obtained from 26 gonarthritis patients (13 RA, 13 non-RA) attending the rheumatology unit for therapeutic joint aspiration. Isolated neutrophils were stimulated by a formylated tripeptide (fMLF) or by microbeads coated with collagen-I. Formation of superoxide-anion-derived reactive oxygen species (ROS) was studied by luminol-enhanced chemiluminescence. Paired samples of blood and SF neutrophils from patients with active arthritis were compared with blood neutrophils from patients in remission and from 47 healthy blood donors.

    Results: SF neutrophils from patients with RA, but not from non-RA patients, showed high baseline intracellular ROS production. Blood neutrophils from arthritis patients in remission existed in a primed state as revealed by more rapid oxidative response after collagen-bead challenge and a more pronounced response after fMLF stimulation compared to healthy blood donors. Blood neutrophils from RA patients with ongoing gonarthritis, however, did not differ from healthy blood donors concerning oxidative activation, whereas blood neutrophils from non-RA patients with gonarthritis showed a significantly lower peak ROS production.

    Conclusions: A novel finding with pathogenetic implications in our study is that SF neutrophils from patients with RA, but not other arthritides, are activated and produce ROS intracellularly. This implies that synovial neutrophils in RA are engaged in the processing of endocytosed material.

  • 9.
    Cedergren, Jan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Oxidative activation of human neutrophils by type-1-collagen-coated particles is influenced by nitric oxide production and modulated by endogenous arginase2007In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673Article in journal (Refereed)
  • 10.
    Dahle, Charlotte
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Åberg, A K
    Örebro.
    Jalal, A
    Örebro.
    Olcén, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology.
    Methods of choice for diagnostic antinuclear antibody (ANA) screening: Benefit of adding antigen-specific assays to immunofluorescence microscopy2004In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 22, no 3, p. 241-248Article in journal (Refereed)
    Abstract [en]

    Objectives. To evaluate and compare the performances of three enzyme-immunoassays (EIAs) and a double radial immunodiffusion (DRID) test in addition to immunofluorescence (IF) microscopy for routine laboratory screening of patient sera sent for antinuclear antibody (ANA) analysis. Methods. 3079 consecutive patient sera sent for routine testing of ANA were analysed by IF microscopy on HEp-2 cells (IF-ANA), three different ANA-EIAs, and a DRID test for antibodies against extractable nuclear antigens. The IF-ANA and DRID tests were regarded as reference methods. Results. By IF-ANA and/or DRID, 375 sera (12%) turned out ANA-positive. A further 171 sera (6%) were positive by EIA, but could not be confirmed either by IF microscopy or DRID. 32 of the 375 ANA-positive (9%) sera were negative by IF microscopy, but had precipitating antibodies against Ro/SS-A (52 and/or 60 kD). Conclusions. Different assays for ANA analysis give overlapping results to a certain extent, but are by no means interchangeable. Thus, different ANA tests reflect different aspects of these autoantibodies. The diagnostic utility of ANA testing still mainly refers to IF-microscopy and precipitin tests. IF-ANA should not be abandoned as the golden standard in clinical routine, until diagnostic and classification criteria for systemic lupus erythematosus and other systemic inflammatory autoimmune diseases have been revised. However, in addition we strongly advocate that a specific test for anti-Ro/SS-A antibodies is always included.

  • 11.
    Dahlström, Örjan
    et al.
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine . Linköping University, Faculty of Health Sciences.
    Hass, Ursula
    Linköping University, Department of Medicine and Health Sciences, Health Technology Assessment. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Timpka, Toomas
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Designing a decision support system for existing clinical organizational structures: Considerations from a rheumatology clinic2006In: Journal of medical systems, ISSN 0148-5598, E-ISSN 1573-689X, Vol. 30, no 5, p. 325-331Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify the social and organizational requirements for a decision support system (DSS) to be implemented in a clinical rheumatology setting, utilizing data-mining techniques. Field observations and focus group interviews were used for data collection. The decision-making was found to be situated, patient-focused, and long-term in nature. At the same time, the main part of peer-to-peer communication was informal. Patient records were involved in almost every decision. The conclusion is that the main challenges, when introducing a DSS at a rheumatology unit, are adapting the system to informal communication structures and integrating it with patient records. Considering incentive structures, understanding workflow and incorporating awareness are relevant issues when addressing these issues in future studies.

  • 12.
    Dahlström, Örjan
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Pain and Rehabilitation Centre.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Timpka, Toomas
    Linköping University, Department of Medical and Health Sciences, Division of Preventive and Social Medicine and Public Health Science.
    Prognostic rule generation controlling for treatment in early rheumatoid arthritis2009Conference paper (Other academic)
  • 13.
    Dahlström, Örjan
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Cognition, Development and Disability. Linköping University, Faculty of Arts and Sciences.
    Timpka, Toomas
    Linköping University, Department of Medical and Health Sciences, Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Public Health Sciences, Centre for Public Health Sciences.
    Hass, Ursula
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences.
    A simple method for heuristic modeling of expert knowledge in chronic disease: identification of prognostic subgroups in rheumatology2008In: eHealth Beyond the Horizon – Get IT There, IOS Press, 2008, Vol. 136, p. 157-162Conference paper (Refereed)
    Abstract [en]

    Identification of prognostic subgroups is of key clinical interest at the early stages of chronic disease. The aim of this study is to examine whether representation of physicians' expert knowledge in a simple heuristic model can improve data mining methods in prognostic assessments of patients with rheumatoid arthritis (RA). Five rheumatology consultants' experiences of clinical data patterns among RA patients, as distinguished from healthy reference populations, were formally represented in a simple heuristic model. The model was used in K-mean-clustering to determine prognostic subgroups. Cross-sectional validation using physician's global assessment scores indicated that the simple heuristic model performed better than crude data made in identification of prognostic subgroups of RA patients. A simple heuristic model of experts' knowledge was found useful for semi-automatic data mining in the chronic disease setting. Further studies using categorical baseline data and prospective outcome variables are warranted and will be examined in the Swedish TIRA-program.

  • 14.
    Dahlström, Örjan
    et al.
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Timpka, Toomas
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Prognostic components and predictive modelling of prognosis in early RAManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: There is a need for tools that are easy to use in clinical practice supporting decision making upon treatment in early rheumatoid arthritis (RA). Aim: The aim was to identify components of prognosticators in early RA and to identify individual patients with a poor prognosis as early as possible.

    Methods: Two cohorts from the Swedish TIRA project including 320+408 patients with recent onset RA were included in the study. Disease activity was measured by C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the 28-joint count disease activity score (DAS-28), and by the physicians’ global assessment of disease activity (PGA). Disability was assessed as activity limitation by the Swedish version of the Health Assessment Questionnaire (HAQ) and impairment was reported by pain on a visual analogue scale of 0–100 mm. Serological markers were rheumatoid factor (RF) and anti-CCP. RF was measured at the time for diagnosis, and anti-CCP at the time of diagnosis or at one or some of the follow-ups. If at least one anti-CCP test was positive, the patient was judged to be anti-CCP-positive. Assuming different clinical practice in the different cohorts, two different treatment strategies were assumed based on clinical practice in real-world settings. Principal Component Analysis and Multiple Linear Regression Analysis were used to identify prognosticators. Prediction rules were identified by data-driven approach, controlling for different treatment strategies.

    Results: Progression of disease and disability measures and inflammation measures the first three months after inclusion predicted a considerable part of DAS-28 at the 1-year follow-up. Serological markers had a larger explanatory power for men than for women. Anti-CCP was a significant predictor for men, but not for women. Two versions of rules, one for women and one for men, predicting good or poor prognosis at one year after inclusion were produced by using measures of disability (Health Assessment Questionnaire), DAS-28, relative change in DAS-28 during first three months, sex, and test of anti-CCP. The rules demanded high prognostic specificity but the prognostic sensitivity was moderate.

    Conclusion: A considerable part of DAS-28 at one year after inclusion could be explained by the first 3 months’ progression of disease, disability and inflammation. Anti-CCP was predictive for men but not for women, and needs further investigation. A decision tree predicting poor prognosis among individual early RA-patients showed high specificity and moderate sensitivity on a validationcohort. The medical informatics approach used, controlling for different treatment strategies, yields promising results and further studies will control for more specific differences in treatment strategies, e.g. different DMARDs initiated.

  • 15.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Eloranta, Maija-Leena
    Uppsala Univ, Uppsala, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Uppsala, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 12, p. 3755-3760Article in journal (Refereed)
    Abstract [en]

    Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.

  • 16.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Ronnelid, Johan
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 5, p. 817-825Article in journal (Refereed)
    Abstract [en]

    Objective. Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. Methods. Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjogren syndrome (n = 54) served as controls. Results. CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fishers exact test revealed striking differences between methods regarding associations with certain disease phenotypes. Conclusion. CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.

  • 17.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Rönnblom, Lars
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Association of Serum C-Reactive Protein Levels With Lupus Disease Activity in the Absence of Measurable Interferon-α and a C-Reactive Protein Gene Variant2014In: Arthritis & rheumatology (Hoboken, N.J.), ISSN 2326-5191, Vol. 66, no 6, p. 1568-1573Article in journal (Refereed)
    Abstract [en]

    Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFN.

    Methods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).

    Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.

    Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene. © 2014 American College of Rheumatology.

  • 18.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Limited Value of Soluble Urokinase Plasminogen Activator Receptor As a Disease Activity Marker in Patients with Systemic Lupus Erythematosus in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S556-S5572011In: ARTHRITIS AND RHEUMATISM, Wiley-Blackwell , 2011, Vol. 63, no 10, p. S556-S557Conference paper (Refereed)
    Abstract [en]

    n/a

  • 19.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus2013In: Translational Research: The Journal of Laboratory and Clinical Medicine, ISSN 1931-5244, E-ISSN 1878-1810, Vol. 162, no 5, p. 287-296Article in journal (Refereed)
    Abstract [en]

    Assessments of disease activity and organ damage in systemic lupus erythematosus (SLE) remain challenging because of the lack of reliable biomarkers and disease heterogeneity. Ongoing inflammation can be difficult to distinguish from permanent organ damage caused by previous flare-ups or medication side effects. Circulating soluble urokinase plasminogen activator receptor (suPAR) has emerged as a potential marker of inflammation and disease severity, and an outcome predictor in several disparate conditions. This study was done to evaluate suPAR as a marker of disease activity and organ damage in SLE. Sera from 100 healthy donors- and 198 patients with SLE fulfilling the 1982 American College of Rheumatology classification criteria and/or the Fries criteria were analyzed for suPAR by enzyme immunoassay. Eighteen patients with varying degree of disease activity were monitored longitudinally. Disease activity was assessed by the SLE disease activity index 2000 and the physicians global assessment. Organ damage was evaluated by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Compared with healthy control subjects, serum suPAR levels were elevated significantly in patients with SLE. No association was recorded regarding suPAR levels and SLE disease activity in cross-sectional or consecutive samples. However, a strong association was observed between suPAR and SDI (P andlt; 0.0005). Considering distinct SDI domains, renal, neuropsychiatric, ocular, skin, and peripheral vascular damage had.a significant effect on suPAR levels. This study is the first to demonstrate an association between serum suPAR and irreversible organ damage in SLE. Further studies are warranted to evaluate suPAR and other biomarkers as predictors of evolving organ damage.

  • 20.
    Eriksson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Andersson, Carina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjögren's syndrome, rheumatoid arthritis and healthy controls2004In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 137, no 3, p. 617-620Article in journal (Refereed)
    Abstract [en]

    Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1-like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL-18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL-18 as well as transforming growth factor (TGF) β1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American-European classification criteria. IL-18 and TGF-β1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL-18 were related (R = 0.52, P = 0.0005). No relation was found neither between IL-18 versus IgG2, IgG3 or IgA, nor between serum TGF-β1 versus any of the immunoglobulins. Since serum levels of IL-18 are related to serum IgG1, IL-18 may be of importance for IgG1 switch and/or release.

  • 21.
    Eriksson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Andersson, Carina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Sjögren´s syndrome with myalgia is associated with subnormal secretion of cytokines by peripheral blood mononuclear cells.2004In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 31, p. 729-735Article in journal (Refereed)
  • 22.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Jacobsson, L
    Malmö University Hospital.
    Lindell, A
    Skogsfrid Primary Care Centre.
    Nilsson, J-A
    Malmö University Hospital.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Improved outcome in Wegener's granulomatosis and microscopic polyangiitis? A retrospective analysis of 95 cases in two cohorts.2009In: Journal of internal medicine, ISSN 1365-2796, Vol. 265, no 4, p. 496-506Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Mortality rates for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have decreased after the introduction of cyclophosphamide. Standardized mortality ratio (SMR) expresses the overall mortality of patients compared with the general population. The aims of this study were to compare survival in an old and a recent cohort of patients with WG and MPA using SMR and to determine predictors for death in both groups combined. DESIGN: Survival analyses were performed by Kaplan-Meier survival curves, SMR and proportional hazards regression models. SETTING: The nephrology and rheumatology clinics at Linköping University Hospital, Sweden. SUBJECTS: All patients diagnosed with WG or MPA in the catchment area during 1978-2005 were divided into two cohorts; patients diagnosed before (n=32, old cohort) and after (n=63, recent cohort) December 31, 1996. RESULTS: The two cohorts differed regarding the proportion of WG (75% vs. 56%, P=0.03) and a tendency for more pronounced kidney involvement in the old cohort: 266 micromol L(-1) (16% dialysis-dependent) vs. 192 micromol L(-1) (5% dialysis-dependent), but were comparable regarding disease severity. SMR at 1 and 5 years were 2.1 (95% CI: 0.43-6.09) and 1.6 (95% CI: 0.6-3.2) in the recent cohort and 5.2 (95% CI: 1.07-15.14) and 2.5 (95% CI: 0.93-5.52) in the old cohort. Five-year survival was 87% and 81%. Serum creatinine, age, end-stage renal disease, diagnosis before 1997 and first relapse were independent predictors for death. CONCLUSION: Patient survival in WG and MPA analysed with SMR may be better than previously believed. Severe renal disease and disease relapse were the major predictors of reduced survival.

  • 23.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register2013In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 3, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Objective Antinuclear antibody (ANA) analysis by immunofluorescence (IF) microscopy remains a diagnostic hallmark of systemic lupus erythematosus (SLE). The clinical relevance of ANA fine-specificities in SLE has been addressed repeatedly, whereas studies on IF-ANA staining patterns in relation to disease manifestations are very scarce. This study was performed to elucidate whether different staining patterns associate with distinct SLE phenotypes.

    Design Observational cohort study.

    Setting One university hospital rheumatology unit in Sweden.

    Participants The study population consisted of 222 cases (89% women; 93% Caucasians), where of 178 met ≥4/11 of the 1982 American College of Rheumatology (ACR-82) criteria. The remaining 20% had an SLE diagnosis based on positive IF-ANA (HEp-2 cells) and ≥2 typical organ manifestations at the time of diagnosis (Fries’ criteria).

    Outcome measures The IF-ANA staining patterns homogenous (H-ANA), speckled (S-ANA), combined homogenous and speckled (HS-ANA), centromeric (C-ANA), nucleolar (N-ANA)±other patterns and other nuclear patterns (oANA) were related to disease manifestations and laboratory measures. Antigen-specificities were also considered regarding double-stranded DNA (Crithidia luciliae) and the following extractable nuclear antigens: Ro/SSA, La/SSB, Smith antigen (Sm), small nuclear RNP (snRNP), Scl-70 and Jo-1 (immunodiffusion and/or line-blot technique).

    Results 54% of the patients with SLE displayed H-ANA, 22% S-ANA, 11% HS-ANA, 9% N-ANA, 1% C-ANA, 2% oANA and 1% were never IF-ANA positive. Staining patterns among patients meeting Fries’ criteria alone did not differ from those fulfilling ACR-82. H-ANA was significantly associated with the 10th criterion according to ACR-82 (‘immunological disorder’). S-ANA was inversely associated with arthritis, ‘immunological disorder’ and signs of organ damage.

    Conclusions H-ANA is the dominant IF-ANA pattern among Swedish patients with SLE, and was found to associate with ‘immunological disorder’ according to ACR-82. The second most common pattern, S-ANA, associated negatively with arthritis and organ damage.

  • 24.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vikerfors, A.
    Karolinska Univ Hosp, Sweden; Swedish Med Prod Agcy, Sweden.
    Grosso, G.
    Karolinska Univ Hosp, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Elvin, K.
    Karolinska Inst, Sweden.
    Gunnarsson, I.
    Karolinska Univ Hosp, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Ronnelid, J.
    Uppsala Univ, Sweden.
    Svenungsson, E.
    Karolinska Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogrens syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

  • 25.
    Ge, Changrong
    et al.
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Tong, Dongmei
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Southern Medical University, Guangzhou, China..
    Liang, Bibo
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm,Southern Medical University, Guangzhou, China.
    Lönnblom, Erik
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Schneider, Nadine
    University Hospital Frankfurt Goethe University, Frankfurt, Germany.
    Hagert, Cecilia
    University of Turku, Finland.
    Viljanen, Johan
    Biomedicinskt centrum, Uppsala University, Uppsala, Sweden.
    Ayoglu, Burcu
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Stawikowska, Roma
    Florida Atlantic University, Jupiter, Florida, USA.
    Nilsson, Peter
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Fields, Gregg B
    Florida Atlantic University, Jupiter, Florida, USA.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kihlberg, Jan
    Uppsala University, Uppsala, Sweden.
    Burkhardt, Harald
    University Hospital Frankfurt Goethe University, Frankfurt, Germany.
    Dobritzsch, Doreen
    Uppsala University, Uppsala, Sweden.
    Holmdahl, Rikard
    Karolinska Institutet, Stockholm, Sweden; University of Turku, Turku, Finland, Southern Medical University, Guangzhou, China.
    Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage2017In: JCI insight, ISSN 2379-3708, Vol. 2, no 13, article id 93688Article in journal (Refereed)
    Abstract [en]

    Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.

  • 26.
    Ge, Changrong
    et al.
    Karolinska Inst, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Liang, Bibo
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Lonnblom, Erik
    Karolinska Inst, Sweden.
    Lundstrom, Susanna L.
    Karolinska Inst, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Ayoglu, Burcu
    KTH Royal Inst Technol, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Malmstrom, Vivianne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Klareskog, Lars
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Toes, Rene E. M.
    Leiden Univ, Netherlands.
    Rispens, Theo
    Univ Amsterdam, Netherlands.
    Dobritzsch, Doreen
    Uppsala Univ, Sweden.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies2019In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71, no 2, p. 210-221Article in journal (Refereed)
    Abstract [en]

    Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.

  • 27.
    Hallert, Eva
    et al.
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Björk, Mathilda
    School of Health Sciences, Jönköping University, Jönköping, Sweden.
    Dahlström, Örjan
    Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Disease activity and disability in women and men with early rheumatoid arthritis: An 8-year follow-up of the Swedish TIRA project2012In: Arthritis Care and Research, ISSN 0893-7524, E-ISSN 1529-0123, Vol. 64, no 8, p. 1101-1107Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To compare women and men regarding course of disease activity and disability over 8 years from diagnosis of recent onset rheumatoid arthritis (RA). PATIENTS AND METHODS: 149 patients were followed for 8 years from RA diagnosis (1996-98) regarding 28-joint count disease activity score (DAS28), pain (visual analogue scale, VAS), grip force, Grip Ability Test (GAT), Signals of Functional Impairment (SOFI hand, upper/lower extremity), walking speed, activity limitation (Health Assessment Questionnaire, HAQ) and prescribed disease-modifying anti-rheumatic drugs (DMARDs). RESULTS: Disease activity pattern over time was similar in women and men, showing improvement during the first year and thereafter a stable situation during 6 years. However, at the 7- and 8-year follow-ups deterioration was seen with a less favourable course in women. HAQ did not differ between sexes at diagnosis, but at all follow-ups women had significantly higher scores than men. Women also had lower grip force and lower walking speed, but higher upper extremity mobility. DMARD prescription was similar for both sexes. Over eight years, disease duration, sex, biologics, grip force, SOFI-hand and pain intensity together explained 43% of the variation in DAS, while grip force, SOFI-lower, GAT and pain intensity could together explain 55% of variations in HAQ. CONCLUSIONS: Disease activity was fairly well managed, but disability gradually deteriorated. Despite similar medication, women had more disability than men. The discrepancy between disease activity and disability indicates unmet needs for multi-professional interventions to prevent progressing disability and patients at risk for disability need to be identified early in the process. © 2012 by the American College of Rheumatology.

  • 28.
    Hallert, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medicine and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Jonsson, Dick
    Linköping University, Department of Medicine and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Rheumatoid arthritis is already expensive during the first year of the disease (the Swedish TIRA Project)2004In: Rheumatology, ISSN 1462-0324, Vol. 43, no 11, p. 1374-1382Article in journal (Refereed)
    Abstract [en]

    Objective. To calculate direct and indirect costs in early rheumatoid arthritis (RA) and to characterize patients generating high and low costs respectively.

    Methods. Two hundred and ninety-seven patients with recent-onset (≤12 months) RA were recruited. Clinical/laboratory data and 'health assessment questionnaire' (HAQ) were registered at inclusion and after 3, 6 and 12 months. After 6 and 12 months, the patients completed a questionnaire concerning health-care utilization and days lost from work. A cut-off point for direct costs was set at 34 000 Swedish kronor (3675) defining one-third of the patients as a high-cost group and two-thirds as low-cost group. Indirect costs were calculated for patients aged <65 yr.

    Results. Two hundred and eleven patients completed the HAQ on both occasions. Indirect costs exceeded direct costs by a factor of 2.3. Sixty three per cent experienced work disability during the first year and were identified as the 'high-indirect-cost group'. Indirect costs accounted for >70% of total costs. Direct costs included ambulatory health care (76%), hospitalization (12%) and medication (9%). Men aged ≥65 yr had low costs compared with younger men and women of all ages. In multiple logistic regression tests, HAQ, high levels of IgM rheumatoid factor (IgM RF) and poor hand function increased the odds of entering the high-direct-cost group, and poor hand function and pain increased the odds of entering the high-indirect-cost group.

    Conclusions. Substantial costs were incurred during the first year after diagnosis of early RA, mainly due to work disability. Indirect costs were two to three times higher than direct costs. High levels of IgM RF, high HAQ score, poor hand function and pain increased the odds of entering high-cost groups.

  • 29.
    Hallert, Eva
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Kalkan, Almina
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Rahmqvist, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Bernfort, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Changes in sociodemographic characteristics at baseline in two Swedish cohorts of patients with early rheumatoid arthritis diagnosed 1996-98 and 2006-092015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 2, p. 100-105Article in journal (Refereed)
    Abstract [en]

    Objectives: To compare baseline sociodemographic characteristics in two rheumatoid arthritis (RA) cohorts enrolled 10 years apart, and to examine differences with respect to the general population. Method: Clinical and sociodemographic data were collected in 320 early RA patients during 1996-98 (TIRA-1) and 467 patients in 2006-09 (TIRA-2). Multivariate logistic regression tests were performed and intercohort comparisons were related to general population data, obtained from official databases. Results: TIRA-2 patients were older than TIRA-1 (58 vs. 56 years). Women (both cohorts, 67%) were younger than men in TIRA-1 (55 vs. 59 years) and in TIRA-2 (57 vs. 61 years). Disease activity was similar but TIRA-2 women scored worse pain and worse on the HAQ. Approximately 73% were cohabiting, in both cohorts and in the general population. Education was higher in TIRA-2 than in TIRA-2 but still lower than in the general population. Women had consistently higher education than men. Education was associated with age, younger patients having higher education. In both cohorts, lower education was associated with increased disability pension and increased sick leave. Sick leave was lower in TIRA-2 than in TIRA-1 (37% vs. 50%) but disability pension was higher (16% vs. 10%). In TIRA-1, 9% of women had disability pension compared with 17% in TIRA-2. A similar decrease in sick leave and an increase in disability pension were also seen in the general population. Older age and a higher HAQ score were associated with increased sick leave and being in the TIRA-2 cohort was associated with decreased sick leave. Conclusions: TIRA-2 patients were slightly older, better educated, had lower sick leave and higher disability pension than those in TIRA-1. Similar changes were seen simultaneously in the general population. Belonging to the TIRA-2 cohort was associated with decreased sick leave, indicating that societal changes are of importance.

  • 30.
    Hallert, Eva
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Kalkan, Almina
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Bernfort, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Early rheumatoid arthritis 6 years after diagnosis is still associated with high direct costs and increasing loss of productivity: the Swedish TIRA project2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no 3, p. 177-183Article in journal (Refereed)
    Abstract [en]

    Objectives: To calculate total costs over 6 years after diagnosis of early rheumatoid arthritis (RA).

    Method: In the longitudinal prospective multicentre TIRA study, 239 patients from seven units, diagnosed in 1996–98, reported regularly on health-care utilization and the number of days lost from work. Costs were obtained from official databases and calculated using unit costs (Swedish kronor, SEK) from 2001. Indirect costs were calculated using the human capital approach (HCA). Costs were inflation adjusted to Euro June 2012, using the Swedish Consumer Price Index and the exchange rate of June 2012. Statistical analyses were based on linear mixed models (LMMs) for changes over time.

    Results: The mean total cost per patient was EUR 14 768 in year 1, increasing to EUR 18 438 in year 6. Outpatient visits and hospitalization decreased but costs for surgery increased from EUR 92/patient in year 1 to EUR 444/patient in year 6. Drug costs increased from EUR 429/patient to EUR 2214/patient, mainly because of the introduction of biologics. In year 1, drugs made up for 10% of direct costs, and increased to 49% in year 6. Sick leave decreased during the first years but disability pensions increased, resulting in unchanged indirect costs. Over the following years, disability pensions increased further and indirect costs increased from EUR 10 284 in year 1 to EUR 13 874 in year 6. LMM analyses showed that indirect costs were unchanged whereas direct costs, after an initial fall, increased over the following years, leading to increasing total costs.

    Conclusions: In the 6 years after diagnosis of early RA, drug costs were partially offset by decreasing outpatient visits but indirect costs remained unchanged and total costs increased.

     

  • 31.
    Hallert, Eva
    et al.
    Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Faculty of Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medicine and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Persson, Jan
    Linköping University, Department of Medicine and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Early predictors of TNFtargeted therapy in women and men with recent onset rheumatoid arthritis (the Swedish TIRA Project)2010Article in journal (Refereed)
  • 32.
    Hallert, Eva
    et al.
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Rehabilitation Center. Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    28-joint count disease activity score at 3 months after diagnosis of early rheumatoid arthritis is strongly associated with direct and indirect costs over the following 4 years: the Swedish TIRA project2011In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 50, no 7, p. 1259-1267Article in journal (Refereed)
    Abstract [en]

    Methods. Three-hundred and twenty patients with early (1 year) RA were assessed at regular intervals. Clinical and laboratory data were collected and patients reported health-care utilization and number of days lost from work. At 3-month follow-up, patients were divided into two groups according to disease activity, using DAS-28 with a cut-off level at 3.2. Direct and indirect costs and EuroQol-5D over the following 4 years were compared between the groups. Multivariate regression models were used to control for possible covariates. Results. Three months after diagnosis, a DAS-28 level of epsilon 3.2 was associated with high direct and indirect costs over the following 4 years. Patients with DAS-28 epsilon 3.2 at 3-month follow-up had more visits to physician, physiotherapist, occupational therapist and nurse, higher drug costs, more days in hospital and more extensive surgery compared with patients with 3-month DAS-28 less than 3.2. Number of days lost from work due to sick leave and permanent work disability was also higher in this group. The effect of disease activity on health-related quality of life was highly significant. In regression models, DAS-28 at 3-month follow-up was significantly associated with costs over the following years. Conclusions. Three months after diagnosis, DAS-28 is an important prognostic marker regarding health-care utilization and costs. Achieving remission or low disease activity 3 months after diagnosis is likely to decrease morbidity, increase quality of life and save costs for the patient and for society over the following years.

  • 33.
    Hallert, Eva
    et al.
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Costs and course of disease and function in early rheumatoid arthritis: a 3-year follow-up (the Swedish TIRA project)2006In: Rheumatology, ISSN 1462-0324, Vol. 45, no 3, p. 325-331Article in journal (Refereed)
    Abstract [en]

    Objective. To calculate direct and indirect costs and to studydisease activity and functional ability over 3 yr in early rheumatoidarthritis (RA).

    Methods. Three hundred and three patients with early (≤1 yr)RA were recruited during a period of 27 months (1996–1998).Data were recorded during 3 yr to assess disease activity, functionalability, medication, health-care utilization and days lost fromwork.

    Results. Within 3 months, improvements were seen regarding allrecorded variables assessing disease activity and functionalability, but 15% had sustained high or moderate disease activitythroughout the study period. Indirect costs exceeded directcosts in all 3 yr. The average direct costs were € 3704 (US$3297) in year 1 and € 2652 (US$ 2360) in year 3. All costs decreased,except those for medication and surgery. Compared with men,women had more ambulatory care visits and used more complementarymedicine. The indirect costs were € 8871 (US$ 7895) in year 1and remained essentially unchanged; this was similar for bothsexes. Almost 50% were on sick leave or early retirement atinclusion. Sick leave decreased but was offset by an increasein early retirement. The 14 patients who eventually receivedTNF inhibitors incurred higher costs even before prescriptionof anti-TNF therapy.

    Conclusion. Disease activity and functional ability improvedwithin 3 months after diagnosis of early RA. Direct costs decreased,except for medication and surgery. Indirect costs remained unchanged.Fifteen per cent of the patients had high or moderate diseaseactivity in all 3 yr, indicating a need for more aggressiveearly anti-rheumatic therapy.

  • 34.
    Hallert, Eva
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Husberg, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Costs, disease and function in recent-onset rheumatoid arthritis - a 3-year-follow-up (the Swedish TIRA-project)2004In: Svenska Läkaresällskapets riksstämma,2004, 2004Conference paper (Refereed)
  • 35.
    Hallert, Eva
    et al.
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    DAS28 at 3 months after diagnosis of early rheumatoid arthritis is strongly associated with direct and indirect costs over the following 4 years. The Swedish TIRA project (Oral presentation)2010Conference paper (Refereed)
  • 36.
    Hallert, Eva
    et al.
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    DAS28 at 3 months after diagnosis of early rheumatoid arthritis is strongly associated with direct and indirect costs over the following 4 years. The Swedish TIRA project (Poster)2010Conference paper (Refereed)
  • 37.
    Hallert, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences.
    Hass, Ursula
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment. Linköping University, The Institute of Technology.
    Skargren, Elisabeth
    Linköping University, Department of Medical and Health Sciences, Physiotherapy. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Comparison between women and men with recent onset rheumatoid arthritis of disease activity and functional ability over two years (the TIRA project)2003In: Annals of the rheumatic diseases, ISSN 0003-4967, Vol. 62, p. 667-670Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the course of recent onset rheumatoidarthritis (RA) and to compare consequences of the disease inmen and women.

    Methods: 284 patients with recent onset RA were followed upprospectively for two years from the time of diagnosis. Measuresof disease activity (for example, 28 joint disease activityscore (DAS28), C reactive protein, morning stiffness, physician’sglobal assessment) and function outcome (for example, rangeof movement, hand function, walking time) were determined. Thepatients’ self reported assessment of functional capacity(Health Assessment Questionnaire (HAQ)) and grading of wellbeingand pain (visual analogue scale) were registered. Changes overtime and differences between men and women were evaluated.

    Results: Improvements were seen for all variables within thefirst three months. Disease activity then remained unchanged.Function variables followed the same pattern during the firstyear, but then tended to worsen. HAQ scores were similar atbaseline, but significantly worse in women than in men at theone and two year follow ups.

    Conclusions: Disease activity was well managed and had improvedsubstantially after two years, whereas function seemed slowlyto deteriorate. Although disease variables were similar formen and women, functional ability (HAQ) had a less favourablecourse in women.

  • 38.
    Hellberg, Sandra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Köpsén, Mattias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kockum, Ingrid
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Olsson, Tomas
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

  • 39.
    Ighe, Anna
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, The Swedish Institute for Disability Research. Linköping University, Faculty of Arts and Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Application of the 2012 systemic lupus international collaborating clinics classification criteria to patients on a Regional Swedish systemic lupus erythematosus register2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 3Article in journal (Refereed)
    Abstract [en]

    Introduction

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

    Methods

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

    Results

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

    Conclusions

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

  • 40. Johansson, AG
    et al.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    IgG immune complex binding to and activation of liver cells.1999In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 121, p. 329-336Article in journal (Refereed)
  • 41.
    Johansson, AG
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    IgG immune complex binding to and activation of liver cells. An in vitro study with IgG immune complexes, Kupffer cells, sinusoidal endothelial cells and hepatocytes2000In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 121, no 4, p. 329-336Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The aim was to study IgG immune complex (IC) binding to isolated hepatocytes, Kupffer cells (KCs) and sinusoidal endothelial cells (SECs). Further, we wished to analyze the capacity of IgG ICs to induce release of reactive oxygen metabolites by the IC-binding liver cells. Methods: ICs were formed between 125I-tyramine-cellobiose-labelled dinitrophenyl-conjugated human serum albumin (125I-TC-DNP10HSA) and polyclonal rabbit IgG antibodies. Binding of ICs to different rat liver cells in suspension was studied at 4░C. Production of reactive oxygen metabolites was measured by luminol-enhanced chemiluminescence at 37░C. Results: IgG mediated binding of 125I-TC-DNP10HSA to both KCs and SECs, but not to hepatocytes. The binding showed saturation kinetics and was blocked by an excess of unlabelled IgG-ICs. IgG-ICs activated KCs, but not SECs, to a chemiluminescence response. Conclusions: Both KCs and SECs bind IgG-ICs in vitro, probably via Fc receptor interaction. IgG-ICs activate KCs to produce reactive oxygen metabolites. The binding of IgG-ICs to isolated hepatocytes is small.

  • 42.
    Kalkan, Almina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Hallert, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Roback, Kerstin
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Carlsson, Per
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Physician Preferences and Variations in Prescription of Biologic Drugs for Rheumatoid Arthritis: A Register-Based Study of 4,010 Patients in Sweden2015In: Arthritis care & research, ISSN 2151-464X, E-ISSN 2151-4658, Vol. 67, no 12, p. 1679-1685Article in journal (Refereed)
    Abstract [en]

    Objective. The prescription of biologic drugs for rheumatoid arthritis (RA) patients has varied considerably across different regions. Previous studies have shown physician preferences to be an important determinant in the decision to select biologic disease-modifying antirheumatic drugs (bDMARDs) rather than nonbiologic, synthetic DMARDs (sDMARDs) alone. The aim of this study was to test the hypothesis that physician preferences are an important determinant for prescribing bDMARDs for RA patients in Sweden. Methods. Using data from the Swedish Rheumatology Quality Register, we identified 4,010 RA patients who were not prescribed bDMARDs during the period 2008-2012, but who, on at least 1 occasion, had an sDMARD prescription and changed treatment for the first time to either a new sDMARD or a bDMARD. Physician preference for the use of bDMARDs was calculated using data on each physicians prescriptions during the study period. The relationship between prescription of a bDMARD and physician preference, controlling for patient characteristics, disease activity, and the physicians local context was evaluated using multivariate logistic regression. Results. When adjusting for patient characteristics, disease activity, and the physicians local context, physician preference was an important predictor for prescription of bDMARDs. Compared with patients of a physician in the lowest preference tertile, patients of physicians in the highest and middle tertiles had an odds ratio for receiving bDMARDs of 2.8 (95% confidence interval [95% CI] 2.13-3.68) and 1.28 (95% CI 1.05-1.57), respectively. Conclusion. Physician preference is an important determinant for prescribing bDMARDs.

  • 43.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Enocsson, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Science & Engineering.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Designed Surface with Tunable IgG Density as an in Vitro Model for Immune Complex Mediated Stimulation of Leukocytes2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 5, p. 3493-3497Article in journal (Refereed)
    Abstract [en]

    We present the design of an in vitro for immune-complex-mediated stimulation of leukocytes and its functional characteristics with respect to monocyte adhesion. The model was based on orientation-controlled immobilization of a humanized IgG1 monoclonal antibody (rituximab) via its interaction with a biotinylated peptide epitope derived from the CD20 marker. The peptide was linked to neutravidin covalently attached to it mixed self-assembled monolayer of carboxyl- and methoxy-terminated oligo(ethylene glycol) alkane thiolates on gold. The surface adhesion propensity of human monocytes (cell line U917) was highly dependent on the lateral IgG density and indicated that there exists a distance between IgG-Fc on the surface where interactions with Fc gamma receptors are optimal. This well-defined platform allows for a careful control of the size and orientation of artificial IgG immune complexes, it is easily made compatible with, for example, cellular imaging, and it will become useful for in vitro studies on the importance of Fc gamma receptor interactions in chronic immune-mediated diseases.

  • 44.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Almroth, Gunnel
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    IgG Rheumatoid Factor Against the Four Human Fc-gamma Subclasses in Early Rheumatoid Arthritis (the Swedish TIRA Project)Manuscript (preprint) (Other academic)
    Abstract [en]

    Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analyzed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG1-4) as sources of antigen. Sera from 40 patients with recent-onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype specific ELISA) were analyzed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF positive RA-sera, IgG-RF was found directed against hIgG1, hIgG4, and most notably, with strikingly high reactivity against hIgG2, but not hIgG3. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgA-RF (r = 0.513) and IgM-RF (r = 0.736) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

  • 45.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Almroth, Gunnel
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    IgG Rheumatoid Factors Against the Four Human Fc-gamma Subclasses in Early Rheumatoid Arthritis (The Swedish TIRA Project)2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 75, no 1, p. 115-119Article in journal (Refereed)
    Abstract [en]

    Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analysed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG14) as sources of antigen. Sera from 40 patients with recent onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype-specific ELISA) were analysed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF-positive RA-sera, IgG-RF was found directed against hIgG1 and hIgG2, but not against hIgG3 or hIgG4. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgM-RF (r = 0.666) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

  • 46.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Ahmadi, Ahmad
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)2005In: Rheumatology, ISSN 1462-0324, Vol. 44, no 10, p. 1294-1298Article in journal (Refereed)
    Abstract [en]

    Objectives. To evaluate the influence of Fc receptor IIIA (FcRIIIA) 158V/F polymorphism on susceptibility and disease severity in early rheumatoid arthritis (RA).

    Methods. In 181 Swedish patients (128 women, 53 men) with RA of recent onset, disease and disability variables such as erythrocyte sedimentation rate, 28-joint disease activity score (DAS28) and health assessment questionnaire (HAQ) scores were monitored regularly during 3 yr. Three hundred and sixty-two controls were recruited from the same geographical area as the patients. FcRIIIA genotyping was performed using denaturing high-performance liquid chromatography.

    Results. In all RA patients, FcRIIIA-158VV was significantly over-represented compared with controls [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.01–3.5, P<0.05]. After stratifying for sex, the difference remained in the male population (OR 3.2, 95%CI 1.03–11, P<0.05) but disappeared among women (OR 1.4, 95%CI 0.7–3.1, P=0.4). In addition, 158VV patients were more likely to exhibit early joint erosions (OR 6.1, 95%CI 1.4–28, P<0.01). At baseline, patients with different FcRIIIA genotypes did not differ with respect to measures of disease activity or functional ability. Thereafter, in male patients with at least one V allele the mean DAS28 and HAQ scores were higher compared with 158FF. In contrast, female patients with at least one 158V allele displayed lower mean DAS28 and HAQ scores compared with those with 158FF.

    Conclusions. In a male population, the FcRIIIA-158VV genotype is associated with an increased risk of developing RA, and the 158V allele with more severe disease in early RA.

  • 47.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Bratt, Johan
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Ernestam, Sofia
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Lampa, Jon
    Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis2007In: Arthritis and Rheumatism, ISSN 0004-3591, Vol. 56, no 2, p. 448-452Article in journal (Refereed)
    Abstract [en]

    Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA).

    Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes.

    Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria.

    Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

  • 48.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Roos Ljungberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ziegelasch, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 3, p. 391-399Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic inflammatory disease where serum analysis of anti-citrullinated peptide/protein antibodies (ACPA) is an important diagnostic/prognostic tool. Levels and changes of ACPA in RA patients have been studied previously in relation to disease course and therapy response, but less is known regarding ACPA isotype changes in early RA. Hence, recent-onset RA patients (n = 231) were subjected to a 3-year clinical and radiological follow-up. Serum samples were serially collected and ACPA isotypes were analysed using the second-generation cyclic citrullinated peptide (CCP) as capture antigen. Changes in ACPA isotype levels and status were related to disease course and pharmacotherapy. At inclusion, 74% of the patients tested positive for ACPA IgG; 55% for immunoglobulin (Ig)A, 37% for secretory IgA (SIgA) and 35% for IgM. The proportion of positive patients decreased significantly at follow-up regarding ACPA SIgA, IgM and IgA. During the initial 3 months, reduction of the 28-joint disease activity score (DAS28) correlated with reduced levels of ACPA IgG (Rho = 0 center dot 242, P = 0 center dot 003), IgA (Rho = 0 center dot 260, P = 0 center dot 008), IgM (Rho = 0 center dot 457, P amp;lt; 0 center dot 001) and SIgA (Rho = 0 center dot 402, P amp;lt; 0 center dot 001). Levels of ACPA SIgA (P = 0 center dot 008) and IgM (P = 0 center dot 021) decreased significantly among patients with good response to treatment, which was not seen regarding ACPA IgA or IgG. Changes in ACPA isotype levels were not associated with radiographic damage. In conclusion, ACPA SIgA and IgM declined rapidly upon anti-rheumatic therapy and correlated with decreased disease activity in recent-onset RA. This may indicate that down-regulation of mucosal immunity to citrullinated proteins/peptides and recruitment of new B cells are key features of therapy responses in early RA.

  • 49.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Strandberg, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Lindroos, Annette
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)2004In: Annals of the Rheumatic Diseases, ISSN 0003-4967, Vol. 63, no 9, p. 1085-1089Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years.

    Methods: 242 patients with recent onset (≤ 1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study "TIRA" 1996-98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician's global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire.

    Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% Cl 34 to 228 U/ml).

    Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.

  • 50.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Wingren, Gun
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)2008In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, p. 415-417Article in journal (Refereed)
    Abstract [en]

    Objectives: The genetic background to RA is incompletely understood.As new cytokine-targeted therapies emerge, early predictorsof disease severity are becoming increasingly important. Theinflammasomes are essential regulators of cytokine production.We investigated whether two polymorphisms in the genes encodingcryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibilityand disease course in RA.

    Methods: Genotype frequencies were assessed in 174 Swedish patientswith early RA and 360 population-based controls without rheumaticdisease. Genotypes were categorized according to the presence(+) or absence (–) of two wild-type alleles and comparedbetween patients and controls. In the RA patients, antibodiestowards cyclic citrullinated peptides (anti-CCP) and the ‘sharedepitope’ (SE) were assessed, and medication and measuresof disease activity were monitored regularly during 3 yrs.

    Results: The combination of CIAS1/TUCAN/–, ascompared with CIAS1/TUCAN +/+, was significantly more commonamong patients than in controls [odds ratio (OR) 2.2, 95% CI1.03–4.6]. This association was strengthened when patientswere divided into anti-CCP+ [OR 2.8 (1.1–6.7)] or presenceof 1 SE copy [OR 2.8 (1.3–6.2)]. At most time-points duringthe 3-yr follow-up, patients with CIAS1/TUCAN/–showed significantly higher disease activity. Furthermore, CIAS1/TUCAN/– patients proved to be much more likely to receiveTNF-blocking therapy [relative risk 20 (2.6–149)].

    Conclusions: Compound polymorphisms in CIAS1 and TUCAN associatewith RA susceptibility and severity. The cryopyrin inflammasomeneeds further attention regarding a possible aetiopathogeneticconnection with RA.

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