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  • 1.
    Ahlstrand, I.
    et al.
    School of Health Sciences, Jönköping University, Jönköping, Sweden.
    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.
    Falkmer, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. School of Health Sciences, Jönköping University, Jönköping, Sweden; School of Occupational Therapy and Social Work, CHIRI, Curtin University, Perth, WA, Australia.
    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.
    Björk, Mathilda
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Rehabilitation Center. School of Health Sciences, Jönköping University, Jönköping, Sweden.
    Pain and activity limitations in women and men with contemporary treated early RA compared to 10 years ago: the Swedish TIRA project2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 4, p. 259-264Article in journal (Refereed)
    Abstract [en]

    Objectives: To study differences regarding pain and activity limitations during the 3 years following diagnosis in women and men with contemporary treated early RA compared with their counterparts who were diagnosed 10 years earlier. Method: This study was based on patients recruited to the Early Intervention in RA (TIRA) project. In the first cohort (TIRA-1) 320 patients were included in time for diagnosis during 1996-1998 and 463 patients were included in the second cohort (TIRA-2) during 2006-2009. Disease activity, pain intensity (Visual Analogue Scale, VAS), bodily pain (BP) in the 36-item Short Form Health Survey (SF-36), activity limitations (Health Assessment Questionnaire, HAQ), and medication were reported at inclusion and at follow-up after 1, 2, and 3 years. Results: Disease activity, pain, and activity limitations were pronounced at inclusion across both genders and in both cohorts, with some improvement observed during the first year after diagnosis. Disease activity did not differ between cohorts at inclusion but was significantly lower at the follow-ups in the TIRA-2 cohort, in which the patients were prescribed traditional disease-modifying anti-rheumatic drugs (DMARDs) and biological agents more frequently. In TIRA-2, patients reported significantly lower pain and activity limitations at all follow-ups, with men reporting lower pain than women. Women reported significantly higher activity limitations at all time points in TIRA-2. Conclusions: Pain and activity limitations were still pronounced in the contemporary treated early RA cohort compared with their counterparts diagnosed 10 years earlier and both of these factors need to be addressed in clinical settings.

  • 2.
    Ahlstrand, Inger
    et al.
    Jonköping University, Sweden.
    Björk, Mathilda
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Rehabilitation Center. Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Jonköping University, Sweden.
    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.
    Falkmer, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Jonköping University, Sweden; Curtin University, Australia.
    Pain and difficulties performing valued life activities in women and men with rheumatoid arthritis2015In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 34, no 8, p. 1353-1362Article in journal (Refereed)
    Abstract [en]

    This study aimed to examine the difficulties with performing valued life activities in relation to pain intensity in women and men with rheumatoid arthritis (RA). In total, 737 persons with RA (73 % women) from three rheumatology units in Sweden responded to a questionnaire measuring performance of 33 valued life activities and self-rated pain. The relationships between performance of valued life activities (VLAs) and pain (measured by visual analogue scale (VAS)) were analysed based on gender. Multiple linear regression analyses were conducted with the total VLA score as dependent variable. Women reported more pain and difficulties in performing valued life activities than men. Across genders, 85 % reported at least one valued life activity affected by RA. Significantly more women than men encountered difficulties in performing some activities such as cooking, gardening and meeting new people. Women reported higher pain intensity (35 mm) than men (31 mm). Almost all 33 difficulty ratings for valued life activities were higher among persons with high pain (greater than 40 mm) than persons with lower pain. Difficulty ratings for valued life activities correlated positively with pain in persons with lower pain, but not among those with high pain. The results highlight the importance of addressing pain, especially among women with RA, as they reported pain to impact on their valued life activities. Interestingly, this was evident also in women with lower levels of pain.

  • 3.
    Ahlstrand, Inger
    et al.
    School of Health and Welfare, Jönköping University, Jönköping, Sweden.
    Vaz, Sharmila
    School of Occupational Therapy & Social Work, CHIRI, Curtin University, Perth, WA, Australia.
    Falkmer, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. School of Health and Welfare, Jönköping University, Jönköping, Sweden.
    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.
    Björk, Mathilda
    Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Self-efficacy and pain acceptance as mediators of the relationship between pain and performance of valued life activities in women and men with rheumatoid arthritis2017In: Clinical Rehabilitation, ISSN 0269-2155, E-ISSN 1477-0873, Vol. 31, no 6, p. 824-834Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study whether personal factors (self-efficacy and pain acceptance) mediate the relationship between pain and performance of valued life activities in persons with rheumatoid arthritis.

    METHODS: Persons with rheumatoid arthritis for at least four years (n = 737; 73% women) answered a questionnaire measuring self-efficacy, pain acceptance, performance of valued life activities, and self-rated pain. Relationships among these constructs were explored using univariate and multivariate analyses. Structural equation modelling was then used to examine the mediational role of personal factors on the relationship between pain and performance of valued life activities.

    RESULTS: A direct negative association between pain and performance of valued life activities was identified (Beta = .34, P < .001). This suggests that people with rheumatoid arthritis who had higher levels of pain has increased difficulties in performing valued life activities. Self-efficacy and activity engagement component of pain acceptance mediated the relationship between pain and performance of valued life activities, however the pain willingness component of pain acceptance did not influence participation in valued life activities.

    CONCLUSION: These findings highlight the importance of considering personal factors, such as pain acceptance and self-efficacy, in facilitating participation in valued life activities.

  • 4.
    Andersson, Malin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Jagervall, Karl
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Not Found:Linkoping Univ, Ctr Med Image Sci and Visualizat CMIV, Linkoping, Sweden; Linkoping Univ, Dept Radiol, Linkoping, Sweden; Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden.
    Eriksson, Per
    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.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Granerus, Göran
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Wang, Chunliang
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    Smedby, Örjan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    How to measure renal artery stenosis - a retrospective comparison of morphological measurement approaches in relation to hemodynamic significance2015In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 15, no 42Article in journal (Refereed)
    Abstract [en]

    Background: Although it is well known that renal artery stenosis may cause renovascular hypertension, it is unclear how the degree of stenosis should best be measured in morphological images. The aim of this study was to determine which morphological measures from Computed Tomography Angiography (CTA) and Magnetic Resonance Angiography (MRA) are best in predicting whether a renal artery stenosis is hemodynamically significant or not. Methods: Forty-seven patients with hypertension and a clinical suspicion of renovascular hypertension were examined with CTA, MRA, captopril-enhanced renography (CER) and captopril test (Ctest). CTA and MRA images of the renal arteries were analyzed by two readers using interactive vessel segmentation software. The measures included minimum diameter, minimum area, diameter reduction and area reduction. In addition, two radiologists visually judged the diameter reduction without automated segmentation. The results were then compared using limits of agreement and intra-class correlation, and correlated with the results from CER combined with Ctest (which were used as standard of reference) using receiver operating characteristics (ROC) analysis. Results: A total of 68 kidneys had all three investigations (CTA, MRA and CER + Ctest), where 11 kidneys (16.2 %) got a positive result on the CER + Ctest. The greatest area under ROC curve (AUROC) was found for the area reduction on MRA, with a value of 0.91 (95 % confidence interval 0.82-0.99), excluding accessory renal arteries. As comparison, the AUROC for the radiologists visual assessments on CTA and MRA were 0.90 (0.82-0.98) and 0.91 (0.83-0.99) respectively. None of the differences were statistically significant. Conclusions: No significant differences were found between the morphological measures in their ability to predict hemodynamically significant stenosis, but a tendency of MRA having higher AUROC than CTA. There was no significant difference between measurements made by the radiologists and measurements made with fuzzy connectedness segmentation. Further studies are required to definitely identify the optimal measurement approach.

  • 5.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Per
    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.
    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.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2242Article in journal (Refereed)
    Abstract [en]

    In mice, B1 and marginal zone (MZ) B-cells play an important role in prevention of autoimmunity through production of regulatory cytokines and natural antibodies. There is limited knowledge about the human counterparts of these cells. We therefore investigated functions of MZ-like B-cells and the frequency of circulating MZ-like and Bl-like B-cells in healthy controls (HC), as well as in patients with autoimmune vasculitis to learn more about the role of these cells in autoimmune disease. After stimulation with CpG oligodeoxynucleotides (ODN) of class B in vitro, MZ-like B-cells were the main producers of IgM whereas switched memory B-cells primarily produced IgG and IgA. TNF and IL-10 were produced by both MZ-like and switched memory B-cells. Neither antibody nor TNF/IL-10 production by the B-cell subsets differed between patients and HC. Patients with autoimmune vasculitis, irrespective of disease activity, had lower percentage and absolute numbers of circulating MZ-like B-cells, and lower absolute numbers of B1-like B-cells. The percentage of B1-like B-cells was reduced during active disease. These findings remained significant when the analysis was confined to active treatment-naive patients (disease onset).Our results suggest that human innate-like B-cells might have a physiological role in prevention of autoimmunity.

  • 6.
    Arkema, Elizabeth V
    et al.
    1Clinical Epidemiology Unit, Department of Medicine, Solna Karolinska Institute, Stockholm.
    Jönsen, Andreas
    Department of Clinical Sciences, Lund University, Lund.
    Rönnblom, Lars
    Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm.
    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.
    Simard, Julia F
    Clinical Epidemiology Unit, Department of Medicine, Solna Karolinska Institute, Stockholm.
    Case definitions in Swedish register data to identify systemic lupus erythematosus2016In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 1Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop and investigate the utility of several different case definitions for systemic lupus erythematosus (SLE) using national register data in Sweden.

    METHODS: The reference standard consisted of clinically confirmed SLE cases pooled from four major clinical centres in Sweden (n=929), and a sample of non-SLE comparators randomly selected from the National Population Register (n=24 267). Demographics, comorbidities, prescriptions and autoimmune disease family history were obtained from multiple registers and linked to the reference standard. We first used previously published SLE definitions to create algorithms for SLE. We also used modern data mining techniques (penalised least absolute shrinkage and selection operator logistic regression, elastic net regression and classification trees) to objectively create data-driven case definitions. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the case definitions identified.

    RESULTS: Defining SLE by using only hospitalisation data resulted in the lowest sensitivity (0.79). When SLE codes from the outpatient register were included, sensitivity and PPV increased (PPV between 0.97 and 0.98, sensitivity between 0.97 and 0.99). Addition of medication information did not greatly improve the algorithm's performance. The application of data mining methods did not yield different case definitions.

    CONCLUSIONS: The use of SLE International Classification of Diseases (ICD) codes in outpatient clinics increased the accuracy for identifying individuals with SLE using Swedish registry data. This study implies that it is possible to use ICD codes from national registers to create a cohort of individuals with SLE.

  • 7.
    Arkema, Elizabeth V
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Palmsten, Kristin
    University of California, San Diego, USA.
    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.
    Svenungsson, Elisabet
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Salmon, Jane E
    Weill Cornell Medical College, New York, New York.
    Simard, Julia F
    Stanford School of Medicine, Stanford, California, USA ;Karolinska Institute, Stockholm, Sweden.
    What to Expect When Expecting With Systemic Lupus Erythematosus (SLE): A Population-Based Study of Maternal and Fetal Outcomes in SLE and Pre-SLE.2016In: Arthritis care & research, ISSN 2151-464X, E-ISSN 2151-4658, Vol. 68, no 7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess maternal and fetal outcomes associated with subclinical (pre-systemic lupus erythematosus [SLE] and SLE presenting up to 5 years postpartum) and prevalent maternal SLE during pregnancy compared with the general population.

    METHODS: This prospective cohort study used population-based Swedish registers to identify 13,598 women with first singleton pregnancies registered in the Medical Birth Register (551 prevalent SLE, 65 pre-SLE within 0-2 years, 133 pre-SLE within 2-5 years, and 12,847 general population). SLE was defined as ≥2 SLE-coded discharge diagnoses in the patient register with ≥1 diagnosis from a specialist. Unadjusted risks of adverse pregnancy or birth outcomes were calculated by SLE status, and Cochran-Armitage tests evaluated trend across exposure groups.

    RESULTS: Maternal outcomes such as preeclampsia, hypothyroidism, stroke, and infection were more common among women with SLE. Sixteen percent of prevalent-SLE pregnancies were diagnosed with preeclampsia compared with 5% of those from the general population. Among the pre-SLE women, preeclampsia was found in 26% of those with SLE within 2 years postpartum and 13% in those with SLE within 2-5 years postpartum. Similarly, infant outcomes, such as preterm birth, infection, and mortality, were worse among those born to mothers with prevalent SLE and pre-SLE during pregnancy. The test for trend was significant for most outcomes.

    CONCLUSION: Our data demonstrate that adverse maternal and fetal outcomes are more common in SLE pregnancies. Furthermore, these unfavorable outcomes are observed in pregnancies occurring prior to the diagnosis of SLE. Thus, the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to these pregnancy complications.

  • 8.
    Arkema, Elizabeth V
    et al.
    Clinical Epidemiology Unit, Karolinska Institutet, Stockholm.
    Rossides, Marios
    Clinical Epidemiology Unit, Karolinska Institutet, Stockholm.
    Von Euler, Mia
    Karolinska Institutet, Stockholm, Sweden.
    Svenungsson, Elisabet
    Rheumatology Unit, Karolinska Institutet, Stockholm.
    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.
    Simard, Julia F
    Karolinska Institutet, Stockholm, Sweden, Stanford School of Medicine, Stanford, California, USA.
    Response to 'Increased stroke incidence in systemic lupus erythematosus patients"2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 10, article id UNSP e72Article in journal (Refereed)
  • 9.
    Arkema, Elizabeth V.
    et al.
    Karolinska Institute, Sweden.
    Svenungsson, Elisabet
    Karolinska Institute, Sweden.
    Von Euler, Mia
    Karolinska Institute, 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.
    Simard, Julia F.
    Karolinska Institute, Sweden; Stanford School Med, CA USA; Stanford School Med, CA USA.
    Stroke in systemic lupus erythematosus: a Swedish population-based cohort study2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 9, p. 1544-1549Article in journal (Refereed)
    Abstract [en]

    Objective To study the occurrence of ischaemic and haemorrhagic stroke in systemic lupus erythematosus (SLE) compared with the general population by age, sex and time since SLE diagnosis Methods Adults with incident SLE were identified from the Swedish National Patient Register (NPR, n=3390) and general population comparators from the Total Population Register were matched on age, sex and county (n=16730). Individuals were followed prospectively until first of death, December 2013, emigration or incident stroke (identified from the NPR, Cause of Death Register and the Stroke Register). Incidence rates, rate differences and HR were estimated comparing SLE with non-SLE. Estimates were stratified by sex, age and time since diagnosis. Results We observed 126 strokes in SLE and 304 in the general population. Individuals with SLE had a twofold increased rate of ischaemic stroke compared with the general population (HR 2.2; 95% CI 1.7 to 2.8). The HR for intracerebral haemorrhage was 1.4 (95% CI 0.7 to 2.8). There was effect modification by sex and age, with the highest HRs for females and individuals amp;lt;50 years old. The HR for ischaemic stroke was highest in the first year of follow-up (3.7; 95% CI 2.1 to 6.5). Conclusions The relative risk of ischaemic stroke in SLE was more than doubled compared with the general population, and importantly, the highest relative risks were observed within the first year after SLE diagnosis. Thus, the first encounter with patients presents an opportunity for rheumatologists to screen for risk factors and intervene.

  • 10.
    Bentow, C.
    et al.
    Inova Diagnost, CA USA.
    Lakos, G.
    Inova Diagnost, CA USA.
    Martis, P.
    Inova Diagnost, CA USA.
    Wahl, E.
    Inova Diagnost, CA USA.
    Garcia, M.
    Hospital Clin Barcelona, Spain.
    Vinas, O.
    Hospital Clin Barcelona, Spain.
    Espinosa, G.
    Hospital Clin Barcelona, Spain.
    Cervera, R.
    Hospital Clin Barcelona, Spain.
    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.
    Carmona-Fernandes, D.
    University of Lisbon, Portugal.
    Santos, M. J.
    University of Lisbon, Portugal.
    Hanly, J. G.
    Dalhousie University, Canada.
    Mahler, M.
    Inova Diagnost, CA USA.
    International multi-center evaluation of a novel chemiluminescence assay for the detection of anti-dsDNA antibodies2016In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 25, no 8, p. 864-872Article in journal (Refereed)
    Abstract [en]

    Objective: Anti-double stranded desoxyribonucleic acid (anti-dsDNA) antibodies are considered fairly specific for systemic lupus erythematosus (SLE) and their quantification is useful for the clinical management of SLE patients. We assessed the diagnostic performance of the QUANTA Flash dsDNA chemiluminescent immunoassay (CIA) in comparison to an ELISA, using patients from five participating countries. The main focus was to evaluate the correlation between anti-dsDNA antibody results from the CIA and global SLE disease activity, as measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). Patients and methods: A total of 1431 samples (SLE, n=843; disease controls, n=588) from five countries (Canada, USA, Portugal, Sweden and Spain) were tested with QUANTA Flash dsDNA (Inova Diagnostics, San Diego, CA, USA). Data obtained with the QUANTA Lite dsDNA SC ELISA (Inova Diagnostics) were available for samples from three sites (Canada, USA and Sweden, n=566). The SLEDAI-2K scores were available for 805 SLE patients and a cut-off ofamp;gt;4 was used to define active disease. Results: QUANTA Flash dsDNA had a sensitivity of 54.3% for the diagnosis of SLE, combined with 89.8% specificity. Anti-dsDNA antibody levels were significantly higher (pamp;lt;0.0001) in active SLE (SLEDAI-2Kamp;gt;4; n=232; median value 83.0IU/mL) versus the inactive patients (n=573; median value 22.3IU/mL), and the SLEDAI-2K scoring correlated with their dsDNA antibody levels (Spearmans rho=0.44, pamp;lt;0.0001). Similar but less pronounced findings were also found for the ELISA, in relation to disease activity. Conclusions: The QUANTA Flash dsDNA assay showed good clinical performance in a large international multi-center study. Additionally, the strong correlation between anti-dsDNA antibody results and SLEDAI-2K scores supported the potential utility of QUANTA Flash dsDNA for monitoring disease activity.

  • 11.
    Bergström, Maria
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy. Linköping University, Faculty of Medicine and Health Sciences.
    Ahlstrand, Inger
    Jönköping University, Sweden.
    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.
    Falkmer, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Jonköping University, Sweden; Curtin University, Australia.
    Börsbo, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Björk, Mathilda
    Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Like the worst toothache you've had - How people with rheumatoid arthritis describe and manage pain2017In: Scandinavian Journal of Occupational Therapy, ISSN 1103-8128, E-ISSN 1651-2014, Vol. 24, no 6, p. 468-476Article in journal (Refereed)
    Abstract [en]

    Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease often associated with disability. Despite new treatments, pain and activity limitations are still present. Objectives: To describe how persons with RA experience and manage pain in their daily life. Methods: Seven semi-structured focus groups (FGs) were conducted and analyzed using content analysis. Results: The analysis revealed four categories: 1) Pain expresses itself in different ways referred to pain as overwhelming, aching or as a feeling of stiffness. 2) Mitigating pain referred to the use of heat, cold, medications and activities as distractions from the pain. 3) Adapting to pain referred to strategies employed as coping mechanisms for the pain, e.g. planning and adjustment of daily activities, and use of assistive devices. 4) Pain in a social context referred to the participants social environment as being both supportive and uncomprehending, the latter causing patients to hide their pain. Conclusions: Pain in RA is experienced in different ways. This emphasizes the multi-professional team to address this spectrum of experiences and to find pain management directed to the individual experience that also include the persons social environment.

  • 12.
    Bjurehed, Linda
    et al.
    Linköping University.
    Brodin, Nina
    Karolinska Institutet, Huddinge, Sweden; Danderyd Hospital, Stockholm, Sweden.
    Nordenskiold, Ulla
    Gothenburg University, Gothenburg, Sweden.
    Björk, Mathilda
    Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Improved Hand Function, Self-Rated Health, and Decreased Activity Limitations: Results After a Two-Month Hand Osteoarthritis Group Intervention2018In: Arthritis care & research, ISSN 2151-464X, E-ISSN 2151-4658, Vol. 70, no 7, p. 1039-1045Article in journal (Refereed)
    Abstract [en]

    Objective

    To evaluate the effects on hand function, activity limitations, and self‐rated health of a primary care hand osteoarthritis (OA) group intervention. Hand OA causes pain, impaired mobility, and reduced grip force, which cause activity limitations. OA group interventions in primary care settings are sparsely reported.

    Methods

    Sixty‐four individuals with hand OA agreed to participate; 15 were excluded due to not fulfilling the inclusion criteria. The 49 remaining (90% female) participated in an OA group intervention at a primary care unit with education, paraffin wax bath, and hand exercise over a 6‐week period. Data were collected at baseline, end of intervention, and after 1 year. Instruments used were the Grip Ability Test (GAT), the Signals of Functional Impairment (SOFI), dynamometry (grip force), hand pain at rest using a visual analog scale (VAS), the Patient‐Specific Functional Scale (PSFS), the Quick Disabilities of the Arm, Shoulder, and Hand (Quick‐DASH), and the EuroQol VAS (EQ VAS). Data were analyzed using nonparametric statistics.

    Results

    Hand function, activity limitation, and self‐rated health significantly improved from baseline to end of intervention, grip force (right hand: P < 0.001; left hand: P = 0.008), SOFI (P = 0.011), GAT (P < 0.001), hand pain at rest (P < 0.001), PSFS (1: P = 0.008, 2: P < 0.001, and 3: P = 0.004), Quick‐DASH (P = 0.001), and EQ VAS (P = 0.039), and the effects were sustained after 1 year.

    Conclusion

    The hand OA group intervention in primary care improves hand function, activity limitation, and self‐rated health. The benefits are sustained 1 year after completion of the intervention.

  • 13.
    Björk, Mathilda
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Rehabilitation Center. Jonköping University, Sweden.
    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.
    Wetterö, Jonas
    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. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Quality of life and acquired organ damage are intimately related to activity limitations in patients with systemic lupus erythematosus2015In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 16, no 188Article in journal (Refereed)
    Abstract [en]

    Background: Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disease, characterized by episodes of disease flares and remissions over time, which may restrain affected patients ability to perform daily activities. The purpose of the present study was to characterize variation in activity limitations among well-defined SLE patients, and to describe disease phenotypes, acquired organ damage and their relations to activity limitation and self-reported health, respectively. Methods: The disease phenotypes were organized into 4 different clinical groups and logistic regression analyses were used to identify how an elevated health assessment questionnaire (HAQ) score was related to disease variables such as phenotypes, disease activity and damage accrual. Correlation and multiple linear regression analyses were used to examine the association between each group of variables - background variables, disease variables and self-reported measurements - and the degree of elevated HAQ. Results: We found a higher proportion of activity limitation in patients with skin and joint involvement compared to others. The presence of activity limitation, as detected by the HAQ instrument, was significantly associated with quality of life (EuroQol-5D) and accrual of organ damage using the Systemic Lupus International Collaborative Clinics/ACR damage index. Conclusions: The findings highlight the differing requirements of the multi-professional rehabilitation interventions for the various SLE phenotypes in order to optimize the clinical care of the patients.

  • 14.
    Björk, Mathilda
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    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.
    Valtersson, Eva
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health.
    Östlund, Gunnel
    School of Health Care and Social Welfare, Mälardalen University, Eskilstuna, Sweden.
    Stenström, Birgitta
    Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sverker, Annette
    Linköping University, Department of Social and Welfare Studies, Social Work. Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health.
    Foot barriers in patients with early rheumatoid arthritis: an interview study among Swedish women and men2018In: Arthritis care & research, ISSN 2151-464X, E-ISSN 2151-4658, Vol. 70, no 9, p. 1348-1354Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Foot impairments are related to reduced mobility and participation restrictions in daily activities in patients with established rheumatoid arthritis (RA). The new biological medications are effective and reduce disease activity, but not disability to the same extent. Foot impairments are assumed to be related to participation restrictions also in patients with early RA, diagnosed after the introduction of biological medications. The knowledge of foot impairments needs to be more explored after the introduction of biological disease-modifying drugs (bDMARDs). The aim of this study was to explore the patients' perspective of foot impairments related to early RA.

    METHODS: The sample included 59 patients (20-63 years) who were interviewed about participation dilemmas in daily life using the Critical Incident Technique. The interviews were audio-recorded and transcribed. Data related to foot impairments were extracted and analyzed thematically. A research partner validated the analysis. The study was approved by the Regional Ethics Committee.

    RESULTS: Patients with early RA described a variety of participation restrictions related to foot impairments: 1) foot hindrances in domestic life, 2) foot impairments influencing work, 3) leisure activities restricted by one's feet 4) struggling to be mobile 5) foot impairments as an early sign of rheumatic disease.

    CONCLUSION: There is a need to focus on foot impairments related to early RA, and for health care professionals to understand these signs. A suggestion for future research is to conduct a longitudinal follow-up of foot impairment related to medication, disease activity and disability in patients diagnosed after the introduction of bDMARDs. This article is protected by copyright. All rights reserved.

  • 15.
    Björk, Mathilda
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy.
    Thyberg, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Valtersson, Eva
    Linköping University, Department of Medical and Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Activity and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Katz, Patricia
    University of California, San Francisco, USA.
    Validation and internal consistency of the Swedish version of the Valued Life Activities scale.2016In: Clinical Rehabilitation, ISSN 0269-2155, E-ISSN 1477-0873, Vol. 30, no 12, p. 1211-1219Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The objective was to create a linguistically and culturally validated Swedish version of the Valued Life Activities scale. The aim was also to describe its content and concurrent validity and its internal consistency in persons with rheumatoid arthritis.

    METHODS: The Valued Life Activities scale was translated to Swedish and culturally adapted. In order to describe the content validity, both the Swedish and original Valued Life Activities scale were linked to the International Classification of Functioning, Disability and Health. The concurrent validity and internal consistency were evaluated in 737 patients with rheumatoid arthritis. To establish concurrent validity, the scale was correlated to disease activity, activity limitations, and life satisfaction. Internal consistency was assessed with Cronbach's alpha.

    RESULTS: The equivalence of meaning between the Swedish and the original Valued Life Activities scale was ensured by harmonization review. Content validity was high when linked to the International Classification of Functioning, Disability and Health. Concurrent validity showed a strong correlation with the activity limitations (r = 0.87), moderate with life satisfaction (r = -0.61), and weak with disease activity (r = 0.38). Internal consistency was excellent (Cronbach's alpha = 0.97).

    CONCLUSIONS: The Swedish Valued Life Activities scale has been tested in a large and well-characterized sample and found to be a linguistically valid and culturally adapted self-reported measure of participation. Content validity of the Valued Life Activities scale was excellent, concurrent validity strong, and the internal consistency excellent. Since both individual preferences and International Classification of Functioning, Disability and Health concepts of disability are taken into account, the Swedish Valued Life Activities scale appears to be a promising new scale addressing important aspects of participation.

  • 16.
    Carlsson Almlöf, Jonas
    et al.
    Uppsala University, Sweden.
    Alexsson, Andrei
    Uppsala University, Sweden.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Sweden.
    Sylwan, Lina
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Backlin, Christofer
    Uppsala University, Sweden.
    Leonard, Dag
    Uppsala University, Sweden.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Tandre, Karolina
    Uppsala University, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Sweden.
    Bengtsson, Christine
    Umeå University, Sweden.
    Jonsen, Andreas
    Lund University, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, 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.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Sandling, Johanna K.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Syvanen, Ann-Christine
    Uppsala University, Sweden.
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individuals SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

  • 17.
    Chalise, Jaya Prakash
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Biggs, Sophie
    Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kalinke, Ulrich
    Twincore, Germany.
    Iacono, Alberta
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Boon, Louis
    EPIRUS Biopharmaceuticals, Utrecht, Netherlands.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritisManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction

    Type I interferon induces tolerance against arthritogenic antigen and protects against antigen induced arthritis (AIA). Regulatory T cells (Treg cells) resolve aberrant immune reaction, maintain self-tolerance and prevent the development of autoimmune diseases. We here investigated the impact of Interferon alpha (IFN-α) on Treg cells development and function during antigen induced arthritis.

    Methods

    For AIA, mice were immunized with methylated bovine serum albumin (mBSA) at day 1 and 7 in presence or absence of IFN-α. At day 21, arthritis was induced by intra-articular injection of mBSA and arthritis was evaluated at day 28. At various days of AIA, CD4, CD25, Foxp3 and CTLA-4 expression was quantified by FACS in blood cells, splenocytes, lymph nodes cells and in ex vivo re-stimulated leucocytes (pooled splenocytes and lymph nodes cells) isolated at same days. To investigate the importance of Treg cells in IFN-α protection in AIA, Foxp3DTReGFP+mice were used, where Treg cells can be depleted transiently by administration of diptherin toxin. CFSE based suppression assay was used to assess the suppression by Treg cells isolated day 4, 10, 20 of AIA against proliferation of mBSA or anti-CD3 stimulated responder T cells (Tresp cells) isolated at same days. For adoptive transfer experiments, 250,000 Treg cells from IFN-α treated or untreated mice day 20 of AIA were intravenously injected to recipient pre-immunized mice without IFN-α treatment during the induction of arthritis. The importance of IFN-α signalling on T cells for the IFN-α protection was evaluated by using CD4-Cre+/- IFNAR flox/flox mice.

    Results

    Protective effects of IFN-α in AIA were associated with significant TGF-β dependent increase in Foxp3+ T cells in blood at day 4 and minor increase of Foxp3+T cells in spleen and lymph node cells. However IFN-α signalling in T cells is not required for IFN-α-protection. Upon ex vivo re-stimulation in presence of IFN-α with mBSA but not anti-CD3, the Treg cells numbers were increased in leucocytes isolated from day 4 and day 10 of AIA. Transient depletion of Treg cells during induction of arthritis (day 21) abolished IFN-α-protection however the protection was not affected when Treg cells are depleted during immunization phase (day 1 and day 7). Against mBSA-stimulated proliferation of Tresp cells, suppression by Treg cells isolated from day 10 and day 20 from IFN-α treated mice are significantly higher than Treg cells from untreated mice. Treg cells isolated from IFN-α or untreated mice at day 20 of AIA when transferred to pre-immunized untreated mice prevent the development of arthritis.

    Conclusion

    Treg cells are critically associated with IFN-α protective effects in AIA. IFN-α enhances TGF-β dependent early development of Treg cells and later IFN-α enhances their suppressive capacity against T cells proliferation in antigen specific manner during AIA.

  • 18.
    Crisci, Elisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Rondahl, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Bergström, Tomas
    University of Gothenburg, Gothenburg, 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.
    Eriksson, Kristina
    University of Gothenburg, Gothenburg, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Complement opsonization promotes HSV-2 infection of human dendritic cells2016In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed)
    Abstract [en]

    Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

    IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

  • 19.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Ernestam, Sofia
    Karolinska Univ Hosp, Sweden.
    Forsblad-DElia, Helena
    Umea Univ, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Lindstrom, Ulf
    Gothenburg Univ, 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.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Uptake of rheumatology biosimilars in the absence of forced switching2018In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, no 5, p. 499-504Article in journal (Refereed)
    Abstract [en]

    Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima (R) and Inflectra (R)) and etanercept (Benepali (R)) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naive patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

  • 20.
    Dieker, Jurgen
    et al.
    Radboud University of Nijmegen, Netherlands.
    Berden, Jo H.
    Radboud University of Nijmegen, Netherlands.
    Bakker, Marinka
    Radboud University of Nijmegen, Netherlands.
    Briand, Jean-Paul
    CNRS, France.
    Muller, Sylviane
    CNRS, France.
    Voll, Reinhard
    University of Medical Centre Freiburg, Germany; University of Medical Centre Freiburg, Germany.
    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.
    Herrmann, Martin
    Friedrich Alexander University of Erlangen Nuremberg, Germany.
    Hilbrands, Luuk B.
    Radboud University of Nijmegen, Netherlands.
    van der Vlag, Johan
    Radboud University of Nijmegen, Netherlands.
    Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0165373Article in journal (Refereed)
    Abstract [en]

    Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of antichromatin/ chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4p(ac)), H2B peptide acetylated at lysine 12 (H2Bp(ac)), H3 peptide trimethylated at lysine 27 (H3p(me)), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4p(ac) showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bp(ac) exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3p(me) appeared not specific for SLE. Anti-H4p(ac) and anti-H2Bp(ac) reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bp(ac) and a more pronounced reactivity with the modified equivalent of H3p(me) and H2Bp(ac). In conclusion, reactivity with H4p(ac) and H2Bp(ac) is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bp(ac) is in particular associated with lupus nephritis.

  • 21.
    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. 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.
    Soluble urokinase plasminogen activator receptor: A valuable biomarker in systemic lupus erythematosus?2015In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 444, p. 234-241Article, review/survey (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a potentially severe autoimmune condition with an unpredictable disease course, often with fluctuations in disease activity over time. Long term inflammation and drug-related side-effects may subsequently lead to permanent organ damage, a consequence which is intimately connected to decreased quality of life and mortality. New lupus biomarkers that convey information regarding inflammation and/or organ damage are thus warranted. Today, there is no clinical biomarker that indicates the risk of damage accrual. Herein we highlight the urokinase plasminogen activator receptor (uPAR) and especially its soluble form (suPAR) that besides having biological functions in e.g. proteolysis, cell migration and tissue homeostasis, recently has emerged as a promising biomarker of inflammation and prognosis of several disorders. A strong association between suPAR and organ damage in SLE was recently demonstrated, and preliminary data (presented in this review) suggests the possibility of a predictive value of suPAR blood levels. The involvement of suPAR in the pathogenesis of SLE remains obscure, but its effects in leukocyte recruitment, phagocytic uptake of dying cells (efferocytosis) and complement regulation suggests that the central parts of the SLE pathogenesis could be regulated by suPAR, and vice versa.

  • 22.
    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.

  • 23.
    Eriksson, Per
    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.
    Andersson, Carina
    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.
    Cassel, Petra
    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.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    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.
    Letter: Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 1, p. 80-83Article in journal (Other academic)
    Abstract [en]

    n/a

  • 24.
    Eriksson, Per
    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.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Frequency, Diagnosis, Treatment, and Outcome of Gastrointestinal Disease in Granulomatosis with Polyangiitis and Microscopic Polyangiitis2018In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 45, no 4, p. 529-537Article in journal (Refereed)
    Abstract [en]

    Objective. Involvement of the gastrointestinal (GI) tract is a rare complication of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The aim was to describe frequency, diagnosis, treatment, and outcome of GI disease in a large series of patients in a single center. Methods. A database that includes all patients with GPA and MPA diagnosed since 1997 in a defined area of southeastern Sweden as well as prevalent older cases and tertiary referral patients was screened for patients with GI disease. Data were retrieved from the patients medical records, and GI manifestations of vasculitis were defined as proposed by Pagnoux, et al in 2005. Results. Fourteen (6.5%) of 216 consecutive patients with GPA/MPA had GI manifestations. Abdominal pain and GI bleeding were the most common symptoms. Radiology was important for detection of GI disease, while endoscopy failed to support the diagnosis in many patients. Because of perforation, 5 patients underwent hemicolectomy or small intestine resection. Primary anastomosis was created in 2/5 and enterostomy in 3/5 patients. One patient had a hemicolectomy because of lower GI bleeding. One sigmoid abscess was treated with drainage, and 1 intraabdominal bleeding condition with arterial coiling. Two patients died from GI disease. GPA and MPA patients with and without GI disease exhibited a similar overall survival. Conclusion. GI disease was found in 6.5% among 216 patients with GPA or MPA. Surgery was judged necessary only in cases with GI perforation or severe bleeding. Multidisciplinary engagement is strongly recommended.

    The full text will be freely available from 2019-05-01 15:16
  • 25.
    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.
    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.

    The full text will be freely available from 2019-09-12 18:55
  • 26.
    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.

  • 27.
    Geetha, Duvuru
    et al.
    Johns Hopkins University, Baltimore, MD, USA.
    Hruskova, Zdenka
    Charles University, Prague, Czech Republic .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Hogan, Jonathan
    Hospital of the University of Pennsylvania, Philadelphia, USA.
    Morgan, Matthew D
    University of Birmingham, UK .
    Cavero, Teresa
    Hospital 12 de Octubre, Madrid, Spain .
    Eriksson, Per
    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.
    Seo, Philip
    John Hopkins University, Baltimore, USA.
    Manno, Rebecca L
    John Hopkins University, Baltimore, USA.
    Dale, Jessica
    University of Birmingham, Birmingham, UK.
    Harper, Lorraine
    University of Birmingham, UK.
    Tesar, Vladimir
    Charles University, Prague, Czech Republic .
    Jayne, David Rw
    Addenbrooke's Hospital, Cambridge, UK .
    Rituximab for treatment of severe renal disease in ANCA associated vasculitis2016In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 29, no 2, p. 195-201Article in journal (Refereed)
    Abstract [en]

    Background

    Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking.

    Methods

    We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events.

    Results

    A total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2 (7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed.

    Conclusions

    This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.

  • 28.
    Gutefeldt, Kerstin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Hedman, Christina A
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Thyberg, Ingrid S M
    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.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Upper extremity impairments in type 1 diabetes with long duration: common problems with great impact on daily life2017In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, p. 1-8Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the prevalence, activity limitations and potential risk factors of upper extremity impairments in type 1 diabetes in comparison to controls.

    METHODS: In a cross-sectional population-based study in the southeast of Sweden, patients with type 1 diabetes <35 years at onset, duration ≥20 years, <67 years old and matched controls were invited to answer a questionnaire on upper extremity impairments and activity limitations and to take blood samples.

    RESULTS: Seven hundred and seventy-three patients (ages 50 ± 10 years, diabetes duration 35 ± 10 years) and 708 controls (ages 54 ± 9 years) were included. Shoulder pain and stiffness, hand paraesthesia and finger impairments were common in patients with a prevalence of 28-48%, which was 2-4-folds higher than in controls. Compared to controls, the patients had more bilateral impairments, often had coexistence of several upper extremity impairments, and in the presence of impairments, reported more pronounced activity limitations. Female gender (1.72 (1.066-2.272), p = 0.014), longer duration (1.046 (1.015-1.077), p = 0.003), higher body mass index (1.08 (1.017-1.147), p = 0.013) and HbA1c (1.029 (1.008-1.05), p = 0.007) were associated with upper extremity impairments.

    CONCLUSIONS: Compared to controls, patients with type 1 diabetes have a high prevalence of upper extremity impairments, often bilateral, which are strongly associated with activity limitations. Recognising these in clinical practise is crucial, and improved preventative, therapeutic and rehabilitative interventions are needed. Implications for rehabilitation Upper extremity impairments affecting the shoulder, hand and fingers are common in patients with type 1 diabetes, the prevalence being 2-4-fold higher compared to non-diabetic persons. Patients with diabetes type 1 with upper extremity impairments have more pronounced limitations in daily activities compared to controls with similar impairments. Recognising upper extremity impairments and activity limitations are important and improved preventive, therapeutic and rehabilitation methods are needed.

  • 29.
    Gutefeldt, Kerstin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Hedman, Christina
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    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.
    Bachrach Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Dysregulated growth hormone-insulin-like growth factor-1 axis in adult type 1 diabetes with long duration2018In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 89, no 4, p. 424-430Article in journal (Refereed)
    Abstract [en]

    ContextIn type 1 diabetes (T1D), dysregulation of the GH-IGF-1 axis has been reported. Whether this is related to upper extremity impairments (UEI) is unknown. ObjectiveExamine differences in GH-IGF-1 axis between T1D on subcutaneous insulin treatment and matched controls without diabetes and possible associations between GH-IGF-1 axis and UEI. DesignCross-sectional population-based study. Patients with T1D, onset amp;lt;35years, duration 20years, amp;lt;67years old and controls were invited to answer questionnaires and take blood samples. SubjectsA total of 605 patients with T1D and 533 controls accepted to participate. OutcomesFasting levels of IGF-1, IGF-1 Z-score, IGFBP-1, IGFBP-3, C-peptide, GH and UEI. ResultsPatients with T1D had lower IGF-1 and IGFBP-3 and higher IGFBP-1 and GH than controls. The difference in IGF-1 persisted with age. Insulin dose was associated with increasing IGF-1 Z-score but even at a very high insulin dose (amp;gt;1U/kg) IGF-1 Z-score was subnormal compared to controls. IGF-1 Z-score was unaffected by glycaemic control (HbA1c) but increased with residual insulin secretion, (C-peptide 1-99 pmol/L). IGFBP-1 was associated with fasting blood glucose, negatively in controls and positively in patients with T1D probably reflecting insulin resistance and insulin deficiency, respectively. There was no association between lower IGF-1 Z-score and UEI in T1D. ConclusionIn adult T1D with fair glycaemic control, the GH-IGF-1 axis is dysregulated exhibiting GH resistance, low IGF-1 and elevated IGFBP-1. Subcutaneous insulin cannot normalize these changes while endogenous insulin secretion has marked effects on IGF-1 pointing to a role of portal insulin.

  • 30.
    Harris, Valerie M.
    et al.
    Oklahoma Medical Research Fdn, USA; University of Oklahoma, USA.
    Sharma, Rohan
    University of Oklahoma,USA; Department Vet Affairs Medical Centre, OK USA.
    Cavett, Joshua
    Oklahoma Medical Research Fdn, USA; University of Oklahoma, USA.
    Kurien, Biji T.
    Oklahoma Medical Research Fdn, USA; University of Oklahoma, USA; Department Vet Affairs Medical Centre, OK USA.
    Liu, Ke
    Cincinnati Childrens Hospital Medical Centre, USA; University of Cincinnati, USA.
    Koelsch, Kristi A.
    Oklahoma Medical Research Fdn, USA; University of Oklahoma, USA; Department Vet Affairs Medical Centre, USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, USA.
    Radfar, Lida
    University of Oklahoma, USA.
    Lewis, David
    University of Oklahoma, USA.
    Stone, Donald U.
    University of Oklahoma, USA; University of Oklahoma, USA.
    Erick Kaufman, C.
    University of Oklahoma, USA.
    Li, Shibo
    University of Oklahoma, USA.
    Segal, Barbara
    University of Minnesota, USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, USA.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, USA; University of Granada, Spain.
    Pons-Estel, Bernardo
    Sanat Parque, Argentina.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Lu, Xianglan
    University of Oklahoma, USA.
    Gottenberg, Jacques-Eric
    Strasbourg University, France.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Cunninghame-Graham, Deborah S.
    Kings Coll London, England.
    Huang, Andrew J. W.
    University of Minnesota, USA.
    Brennan, Michael T.
    Carolinas Medical Centre, USA.
    Hughes, Pamela
    University of Minnesota, MN USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Miceli-Richard, Corinne
    University of Paris 11, France.
    Keystone, Edward C.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Bykerk, Vivian P.
    Hospital Special Surg, NY USA.
    Hirschfield, Gideon
    University of Birmingham, England.
    Xie, Gang
    University of Toronto, Canada.
    Ng, Wan-Fai
    Newcastle University, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Magnusson Bucher, Sara
    Örebro University Hospital, Sweden.
    Eriksson, Per
    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.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Rhodus, Nelson L.
    University of Minnesota, USA.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Rohrer, Michael
    University of Minnesota, USA.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Mariette, Xavier
    University of Paris 11, France.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, USA.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, USA; University of Cincinnati, OH USA; Department Vet Affairs Medical Centre, OH USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, USA; University of Oklahoma, OK 73190 USA.
    Scofield, R. Hal
    Oklahoma Medical Research Fdn, USA; University of Oklahoma, OK 73190 USA; University of Oklahoma, OK 73190 USA; Department Vet Affairs Medical Centre, OK USA.
    Klinefelters syndrome (47,XXY) is in excess among men with Sjogrens syndrome2016In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 168, p. 25-29Article in journal (Refereed)
    Abstract [en]

    Primary Sjogrens syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelters syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47)0(Y, p = 0.0012 by Fishers exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fishers exact test p = NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA. Published by Elsevier Inc.

  • 31.
    Harris, Valerie M.
    et al.
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA.
    Sharma, Rohan
    Univ Oklahoma, OK 73190 USA; US Dept Vet Affairs, OK USA.
    Cavett, Joshua
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA.
    Kurien, Biji T.
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA; US Dept Vet Affairs, OK USA.
    Liu, Ke
    Cincinnati Childrens Hosp Med Ctr, OH 45229 USA; Univ Cincinnati, OH USA.
    Koelsch, Kristi A.
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA; US Dept Vet Affairs, OK USA.
    Rasmussen, Astrid
    Oklahoma Med Res Fdn, OK 73104 USA.
    Radfar, Lida
    Univ Oklahoma, OK 73190 USA.
    Lewis, David
    Univ Oklahoma, OK 73190 USA.
    Stone, Donald U.
    Univ Oklahoma, OK 73190 USA; Univ Oklahoma, OK 73190 USA.
    Kaufman, C. Erick
    Univ Oklahoma, OK 73190 USA.
    Li, Shibo
    Univ Oklahoma, OK 73190 USA; Univ Granada, Spain.
    Segal, Barbara
    Univ Minnesota, MN 55455 USA.
    Wallace, Daniel J.
    Cedars Sinai Med Ctr, CA 90048 USA.
    Weisman, Michael H.
    Cedars Sinai Med Ctr, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Med Ctr, CA 90048 USA.
    Kelly, Jennifer A.
    Oklahoma Med Res Fdn, OK 73104 USA.
    Alarcon-Riquelme, Marta E.
    Oklahoma Med Res Fdn, OK 73104 USA.
    Pons-Estel, Bernardo
    Sanatorio Parque, Argentina.
    Jonsson, Roland
    Univ Bergen, Norway; Haukeland Hosp, Norway.
    Lu, Xianglan
    Univ Oklahoma, OK 73190 USA; Univ Granada, Spain.
    Gottenberg, Jacques-Eric
    Strasbourg Univ, France.
    Anaya, Juan-Manuel
    Univ Rosario, Colombia.
    Cunninghame-Graham, Deborah S.
    Kings Coll London, England; Karolinska Inst, Sweden; Kings Coll London, England.
    Huang, Andrew J. W.
    Univ Minnesota, MN USA.
    Brennan, Michael T.
    Carolinas Med Ctr, NC 28232 USA.
    Hughes, Pamela
    Univ Minnesota, MN USA.
    Alevizos, Ilias
    Natl Inst Dent and Craniofacial Res, MD USA.
    Miceli-Richard, Corinne
    Univ Paris Sud, France.
    Keystone, Edward C.
    Mt Sinai Hosp, Canada; Univ Toronto, Canada.
    Bykerk, Vivian P.
    Hosp Special Surg, NY 10021 USA.
    Hirschfield, Gideon
    Univ Birmingham, England.
    Xie, Gang
    Samuel Lunenfeld Res Inst, Canada; Toronto Gen Res Inst, Canada; Univ Toronto, Canada; Univ Toronto, Canada; Univ Toronto, Canada.
    Siminovitch, Katherine A.
    Samuel Lunenfeld Res Inst, Canada; Toronto Gen Res Inst, Canada; Univ Toronto, Canada; Univ Toronto, Canada; Univ Toronto, Canada.
    Ng, Wan-Fai
    Newcastle Univ, England; Newcastle Univ, England.
    Nordmark, Gunnel
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Bucher, Sara Magnusson
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA.
    Eriksson, Per
    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.
    Omdal, Roald
    Stavanger Univ Hosp, Norway.
    Rhodus, Nelson L.
    Univ Minnesota, MN 55455 USA.
    Rischmueller, Maureen
    Queen Elizabeth Hosp, Australia; Univ Adelaide, Australia.
    Rohrer, Michael
    Univ Minnesota, MN USA.
    Wahren-Herlenius, Marie
    Karolinska Inst, Sweden.
    Witte, Torsten
    Hannover Med Sch, Germany.
    Mariette, Xavier
    Univ Paris Sud, France.
    Lessard, Christopher J.
    Oklahoma Med Res Fdn, OK 73104 USA.
    Harley, John B.
    Cincinnati Childrens Hosp Med Ctr, OH 45229 USA; Univ Cincinnati, OH USA; US Dept Vet Affairs, OH USA.
    Sivils, Kathy L.
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA.
    Scofield, R. Hal
    Oklahoma Med Res Fdn, OK 73104 USA; Univ Oklahoma, OK 73190 USA; Univ Oklahoma, OK 73190 USA; US Dept Vet Affairs, OK USA.
    Correction: Klinefelters syndrome (47,XXY) is in excess among men with Sjogrens syndrome (vol 168, pg 25, 2016)2018In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 187, p. 137-138Article in journal (Other academic)
    Abstract [en]

    n/a

  • 32.
    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.

  • 33.
    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.

  • 34.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala Univ, Sweden.
    Carlsson Almlöf, Jonas
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Padyukov, Leonid
    Karolinska Inst, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, 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.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLADQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 35.
    Jönsen, Andreas
    et al.
    Department of Rheumatology, Lund University, Lund,.
    Hjalte, Frida
    The Swedish Institute for Health Economics, Lund.
    Willim, Minna
    Lunds University, Lund .
    Carlsson, Katarina Steen
    The Swedish Institute for Health Economics, Lund.
    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.
    Svenungsson, Elisabet
    Karolinska University Hospital, K, Karolinska Institutet, Stockholm .
    Leonard, Dag
    Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.
    Bengtsson, Christine
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Pettersson, Susanne
    Karolinska University Hospital, Karolinska Institutet, Stockholm.
    Gunnarsson, Iva
    University Hospital, Karolinska Institutet, Stockholm.
    Zickert, Agneta
    University Hospital, Karolinska Institutet, Stockholm.
    Gustafsson, Johanna T
    University Hospital, Karolinska Institutet, Stockholm.
    Rönnblom, Lars
    Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.
    Petersson, Ingemar F
    Department of Orthopedics, Lund University, Lund.
    Bengtsson, Anders A
    Department of Rheumatology, Lund University, Lund,.
    Nived, Ola
    Department of Rheumatology, Lund University, Lund,.
    Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts.2016In: Seminars in Arthritis & Rheumatism, ISSN 0049-0172, E-ISSN 1532-866X, Vol. 45, no 6, p. 684-690Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVES: The main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden.

    METHODS: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency.

    RESULTS: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941€), of which direct cost was 63,672kr ($10,188 = 7004€) and the indirect cost was 144,883 SEK ($23,181 = 15,937€), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs.

    CONCLUSION: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (=129.5 million €). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs.

  • 36.
    Kalkan, Almina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Hallert, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Roback, Kerstin
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    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.
    Individual variations in treatment decisions by Swedish rheumatologists regarding biological drugs for rheumatoid arthritis2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 4, p. 265-270Article in journal (Refereed)
    Abstract [en]

    Objective: In Sweden, reports indicate surprisingly large regional variation in prescription of biological drugs, despite a growing number of clinical studies describing their beneficial effects and guidelines by professional organizations and agencies. Our objective was to ascertain whether there is also variation between individual rheumatologists in prescribing biologics to patients with rheumatoid arthritis (RA) and to evaluate reasons for treatment choices.

    Methods: Ten hypothetical patient cases were constructed and presented to 26 rheumatologists in five regions in Sweden. The cases were based on actual cases and were thoroughly elaborated by a senior rheumatologist and pre-tested in a pilot study. The respondents were asked whether they would treat the patients with a biological agent (YES/NO) and to explain their decisions.

    Results: The response rate was 26/105; 25%. Treatment choices varied considerably between the rheumatologists, some prescribing biologics to 9/10 patients and others to 2/10. In five of the ten hypothetical cases, approximately half of the respondents would prescribe biologics. No regions with particularly high or low prescription were identified. Both the decision to prescribe biologics, as well as not to prescribe, were mainly motivated by medical reasons. Some rheumatologists also referred to lifestyle-related factors or social function of the patient.

    Conclusion: The choice of initiation of biologics varied substantially among rheumatologists presented with hypothetical patient cases, and there were also disparities between rheumatologists practising at the same clinic. Treatment choices were primarily motivated by medical reasons. This situation raises concerns about a lack of consensus in RA treatment strategies.

  • 37.
    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.

  • 38.
    Kastbom, Alf
    et al.
    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.
    Arlestig, Lisbeth
    Umeå University, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umeå University, Sweden.
    Genetic Variants of the NLRP3 Inflammasome Are Associated with Stroke in Patients with Rheumatoid Arthritis2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 10, p. 1740-1745Article in journal (Refereed)
    Abstract [en]

    Objective. Inflammasomes are intracellular protein complexes important for the production of proinflammatory cytokines. Studies have suggested that the NLRP3 inflammasome influences both the severity of rheumatoid arthritis (RA) and development of atherosclerosis. Therefore, we investigated whether functional genetic variants related to the NLRP3 inflammasome influence the risk of cardiovascular (CV) disease (CVD) in patients with RA. Methods. The incidence of CVD was assessed in 522 patients with established RA by a retrospective survey of medical records in combination with a 6-year prospective followup. NLRP3-Q705K and CARD8-C10X genotypes were analyzed in relation to CVD by logistic regression, adjusting for traditional risk factors, antirheumatic treatment, and age at the onset of RA. Results. Carriage of the NLRP3-Q705K minor allele was associated with an increased risk of stroke/transient ischemic attack (TIA; OR 2.01, 95% CI 1.0-4.1, p = 0.05), while CARD8-C10X was not associated with any type of CV event. Patients with greater than= 1 variant allele in both polymorphisms had an increased risk of CVD when compared with patients without variant alleles present in both polymorphisms (adjusted OR 3.05, 95% CI 1.42-6.54, p = 0.004). Stratification showed that this risk was confined to stroke/TIA (adjusted OR 5.09, 95% CI 2.27-11.44, p less than 0.0001) and not to myocardial infarction (MI)/angina pectoris (adjusted OR 1.58, 95% CI 0.67-3.73). Risk estimates were consistently higher among female patients. Conclusion. Genetic variants of the NLRP3 inflammasome influence the risk of stroke/TIA, but not of MI/angina pectoris in Swedish patients with established RA.

  • 39.
    Kastbom, Alf
    et al.
    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. Karolinska Institute, Sweden.
    Forslind, Kristina
    Helsingborgs Lasarett, Sweden; Skåne University Hospital, Sweden.
    Ernestam, Sofia
    Karolinska Institute, Sweden.
    Geborek, Pierre
    Skåne University Hospital, Sweden.
    Karlsson, Johan A.
    Skåne University Hospital, Sweden.
    Petersson, Ingemar F.
    Lund University, Sweden.
    Saevarsdottir, Saedis
    Karolinska Institute, Sweden.
    Klareskog, Lars
    Karolinska Institute, Sweden.
    van Vollenhoven, Ronald F.
    Karolinska Institute, Sweden.
    Lundberg, Karin
    Karolinska Institute, Sweden.
    Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, no 2, p. 356-361Article in journal (Refereed)
    Abstract [en]

    Objective To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA). Methods Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and a-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression. Results During the 2-year follow-up, the proportion of patients testing positive declined significantly regarding antibodies to cVim, cFib and CEP-1, while anti-CCP antibody occurrence remained stable over time. Turning anti-cVim antibody negative was most common, and anti-cVim antibody seroreversion during the first three months associated with significantly less 2-year radiographic progression compared with patients who remained positive. Median antibody levels of all tested ACPAs declined uniformly during initial methotrexate therapy and following response to add-on therapy, with no significant relation to treatment regimen or radiographic progression. Conclusions The influence of early antirheumatic therapy on ACPA seroreversions was markedly different across specificities, and early disappearance of anti-cVim antibodies associated with better radiological outcome. Thus, these data suggest that the disappearance of particular ACPA reactivities may be beneficial in early RA.

  • 40.
    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.
    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.

  • 41.
    Kottyan, Leah C.
    et al.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA .
    Zoller, Erin E.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Bene, Jessica
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Lu, Xiaoming
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology .
    Kelly, Jennifer A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Rupert, Andrew M.
    Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA..
    Lessard, Christopher J.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology .
    Vaughn, Samuel E.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Marion, Miranda
    Department of Biostatistical Sciences and Center for Public Health Genomics .
    Weirauch, Matthew T.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA..
    Namjou, Bahram
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology .
    Adler, Adam
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Rasmussen, Astrid
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Glenn, Stuart
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Montgomery, Courtney G.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Hirschfield, Gideon M.
    NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK..
    Xie, Gang
    Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada..
    Coltescu, Catalina
    Liver Centre, Toronto Western Hospital, Toronto, ON, Canada..
    Amos, Chris
    Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA..
    Li, He
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology and..
    Ice, John A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Nath, Swapan K.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Mariette, Xavier
    Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France..
    Bowman, Simon
    Rheumatology Department, University Hospital Birmingham, Birmingham, UK..
    Rischmueller, Maureen
    The Queen Elizabeth Hospital, Adelaide, Australia..
    Lester, Sue
    The Queen Elizabeth Hospital, Adelaide, Australia The University of Adelaide, Adelaide, Australia..
    Brun, Johan G.
    Institute of Internal Medicine, University of Bergen, Bergen, Norway Department of Rheumatology, Haukeland University Hospital, Bergen, Norway..
    Gøransson, Lasse G.
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Harboe, Erna
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Omdal, Roald
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Cunninghame-Graham, Deborah S.
    Department of Medical and Molecular Genetics, Kings College London, London, UK..
    Vyse, Tim
    Department of Medical and Molecular Genetics, Kings College London, London, UK..
    Miceli-Richard, Corinne
    Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France..
    Brennan, Michael T.
    Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA..
    Lessard, James A.
    Valley Bone and Joint Clinic, Grand Forks, ND, USA..
    Wahren-Herlenius, Marie
    Department of Medicine, Karolinska Institute, Stockholm, Sweden..
    Kvarnström, Marika
    Department of Medicine, Karolinska Institute, Stockholm, Sweden..
    Illei, Gabor G.
    National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA..
    Witte, Torsten
    Hannover Medical School, Hanover, Germany..
    Jonsson, Roland
    Department of Rheumatology, Haukeland University Hospital, Bergen, Norway Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway..
    Eriksson, Per
    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.
    Nordmark, Gunnel
    Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden..
    Ng, Wan-Fai
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK..
    Anaya, Juan-Manuel
    Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia..
    Rhodus, Nelson N.
    Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, USA..
    Segal, Barbara M.
    Division of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, USA..
    Merrill, Joan T.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    James, Judith A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA..
    Guthridge, Joel M.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Hal Scofield, R
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Division of Veterans Affairs Medical Center, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA..
    Alarcon-Riquelme, Marta
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain..
    Bae, Sang-Cheol
    Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea..
    Boackle, Susan A.
    Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA..
    Criswell, Lindsey A.
    Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA..
    Gilkeson, Gary
    Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA..
    Kamen, Diane L
    Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA..
    Jacob, Chaim O.
    Divison of Gastrointestinal and Liver Diseases, Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA..
    Kimberly, Robert
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Brown, Elizabeth
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Edberg, Jeffrey
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Alarcón, Graciela S.
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Reveille, John D.
    Division of Rheumatology and Clinical Immunogenetics, The Univeristy of Texas Health Science Center at Houston, Houston, TX, USA..
    Vilá, Luis M.
    University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA..
    Petri, Michelle
    Division of Rheumatology, Johns Hopkins, Baltimore, MD, USA..
    Ramsey-Goldman, Rosalind
    Division of Rheumatology, Northwestern University, Chicago, IL, USA..
    Freedman, Barry I.
    Wake Forest School of Medicine, Winston-Salem, NC, USA..
    Niewold, Timothy
    Division of Rheumatology and Immunology, Mayo Clinic, Rochester, MN, USA..
    Stevens, Anne M.
    University of Washington and Seattle Childrens Hospital, Seattle, WA, USA..
    Tsao, Betty P.
    David Geffen School of Medicine, University of California, Los Angeles, CA, USA..
    Ying, Jun
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Mayes, Maureen D.
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Gorlova, Olga Y.
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Wakeland, Ward
    University of Texas Southwestern Medical School, Dallas, TX, USA..
    Radstake, Timothy
    Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands..
    Martin, Ezequiel
    Instituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and..
    Martin, Javier
    Instituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and..
    Siminovitch, Katherine
    Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada Department of Medicine, University of Toronto, Toronto, ON, Canada..
    Moser Sivils, Kathy L.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Gaffney, Patrick M.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Langefeld, Carl D.
    Department of Biostatistical Sciences and Center for Public Health Genomics and..
    Harley, John B.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA..
    Kaufman, Kenneth M.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA..
    The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 2, p. 582-596Article in journal (Refereed)
    Abstract [en]

    Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

  • 42.
    Langefeld, Carl D.
    et al.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Ainsworth, Hannah C.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Comeau, Mary E.
    Wake Forest School Med, NC 27101 USA.
    Marion, Miranda C.
    Wake Forest School Med, NC 27101 USA.
    Howard, Timothy D.
    Wake Forest School Med, NC 27101 USA.
    Ramos, Paula S.
    Medical University of South Carolina, SC 29425 USA.
    Croker, Jennifer A.
    UAB School Med, AL 35294 USA.
    Morris, David L.
    Kings Coll London, England.
    Sandling, Johanna K.
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Carlsson Almlof, Jonas
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Acevedo-Vasquez, Eduardo M.
    University of Nacl Mayor San Marcos, Peru.
    Alarcon, Graciela S.
    UAB School of Medicine, Birmingham, Alabama, USA.
    Babini, Alejandra M.
    Hospital Italiano Cordoba, Argentina.
    Baca, Vicente
    Hospital Pediat Mexico City, Mexico.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Berbotto, Guillermo A.
    Hospital Eva Peron, Argentina.
    Bijl, Marc
    Martini Hospital, Netherlands.
    Brown, Elizabeth E.
    UAB School of Medicine, Birmingham, Alabama, USA..
    Brunner, Hermine I.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    Cardiel, Mario H.
    Centre Invest Clin Morelia, Mexico.
    Catoggio, Luis
    Hospital Italiano Buenos Aires, Argentina.
    Cervera, Ricard
    University of Barcelona, Spain.
    Cucho-Venegas, Jorge M.
    University of Nacl Mayor San Marcos, Peru.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, Sweden.
    DAlfonso, Sandra
    University of Piemonte Orientale, Italy.
    Martins Da Silva, Berta
    University of Porto, Portugal.
    de la Rua Figueroa, Inigo
    Hospital University of Gran Canaria Dr Negrin, Spain.
    Doria, Andrea
    University of Padua, Italy.
    Edberg, Jeffrey C.
    UAB School Med, AL 35294 USA.
    Endreffy, Emoke
    University of Szeged, Hungary; University of Szeged, Hungary.
    Esquivel-Valerio, Jorge A.
    Hospital University of Dr Jose Eleuterio Gonzalez University of Autonom, Mexico.
    Fortin, Paul R.
    University of Laval, Canada.
    Freedman, Barry I.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Frostegard, Johan
    Karolinska Institute, Sweden.
    Garcia, Mercedes A.
    Hospital Interzonal Gen Agudos Gen San Martin, Argentina.
    Garcia de la Torre, Ignacio
    University of Guadalajara, Mexico.
    Gilkeson, Gary S.
    Medical University of South Carolina, SC 29425 USA.
    Gladman, Dafna D.
    Toronto Western Hospital, Canada.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Huggins, Jennifer L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    James, Judith A.
    Hospital Eva Peron, Argentina; University of Oklahoma, OK 73104 USA; University of Oklahoma, OK 73104 USA.
    Kallenberg, Cees G. M.
    University of Medical Centre Groningen, Netherlands.
    Kamen, Diane L.
    Medical University of South Carolina, Charleston, USA.
    Karp, David R.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kovacs, Laszlo
    University of Szeged, Hungary.
    Laustrup, Helle
    Odense University Hospital, Denmark.
    Lauwerys, Bernard R.
    Catholic University of Louvain, Belgium; Catholic University of Louvain, Belgium.
    Li, Quan-Zhen
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Maradiaga-Cecena, Marco A.
    Hospital Gen Culiacan, Mexico.
    Martin, Javier
    CSIC, Spain.
    McCune, Joseph M.
    University of Michigan, MI 48103 USA.
    McWilliams, David R.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Merrill, Joan T.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miranda, Pedro
    Centre Estudios Reumatol, Chile.
    Moctezuma, Jose F.
    Hospital Gen Mexico City, Mexico.
    Nath, Swapan K.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Niewold, Timothy B.
    Mayo Clin, MN 94158 USA.
    Orozco, Lorena
    Institute Nacl Medical Genom INMEGEN, Mexico.
    Ortego-Centeno, Norberto
    Hospital University of San Cecilio, Spain.
    Petri, Michelle
    Johns Hopkins University, MD 21218 USA.
    Pineau, Christian A.
    McGill University, Canada.
    Pons-Estel, Bernardo A.
    Sanatorio Parque, Argentina.
    Pope, Janet
    University of Western Ontario, Canada.
    Raj, Prithvi
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Ramsey-Goldman, Rosalind
    Northwestern University, IL 60611 USA.
    Reveille, John D.
    University of Texas Health Science Centre Houston UTHealth, TX 77030 USA.
    Russell, Laurie P.
    Wake Forest School Med, NC 27101 USA.
    Sabio, Jose M.
    Hospital University of Virgen de las Nieves, Spain.
    Aguilar-Salinas, Carlos A.
    Institute Nacl Ciencias Medical and Nutr Salvador Zubiran, Mexico.
    Scherbarth, Hugo R.
    Autoinmunes HIGA Dr Alende Mar Plata, Argentina.
    Scorza, Raffaella
    Fdn IRCCS CaGranda Osped Ma Repiore Policlin, Italy; University of Milan, Italy.
    Seldin, Michael F.
    UC Davis School Med, CA 95616 USA.
    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.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Thompson, Susan D.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Toloza, Sergio M. A.
    Minist Heatlh, Argentina.
    Truedsson, Lennart
    Lund University, Sweden.
    Tusie-Luna, Teresa
    UNAM Institute Nacl Ciencias Medical and Nutr Salvador Zubir, Mexico.
    Vasconcelos, Carlos
    University of Porto, Portugal.
    Vila, Luis M.
    University of Puerto Rico, PR 00936 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wither, Joan E.
    Toronto Western Hospital, Canada.
    Bhangale, Tushar
    Genentech Inc, CA 94080 USA.
    Oksenberg, Jorge R.
    University of Calif San Francisco, CA 94158 USA; University of Calif San Francisco, CA 94158 USA.
    Rioux, John D.
    University of Montreal, Canada; Montreal Heart Institute, Canada.
    Gregersen, Peter K.
    Feinstein Institute Medical Research, NY 11030 USA.
    Syvanen, Ann-Christine
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Criswell, Lindsey A.
    UCSF School Med, CA 94158 USA.
    Jacob, Chaim O.
    Keck School Medical USC, CA 90033 USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Tsao, Betty P.
    Medical University of South Carolina, SC 29425 USA.
    Schanberg, Laura E.
    Duke University, NC 27708 USA.
    Behrens, Timothy W.
    Genentech Inc, CA 94080 USA.
    Silverman, Earl D.
    Hospital Sick Children, Canada; Hospital Sick Children, Canada; University of Toronto, Canada.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Granada, Spain; Karolinska Institute, Sweden.
    Kimberly, Robert P.
    UAB School Med, AL 35294 USA.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Wakeland, Edward K.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Graham, Robert R.
    Genentech Inc, CA 94080 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Transancestral mapping and genetic load in systemic lupus erythematosus2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16021Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P amp;lt; 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

  • 43.
    Leonard, Dag
    et al.
    Uppsala University, Uppsala, Sweden.
    Svenungsson, Elisabet
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Dahlqvist, Johanna
    Uppsala University, Uppsala, Sweden.
    Alexsson, Andrei
    Rheumatology, Uppsala University, Uppsala, Sweden.
    Ärlestig, Lisbeth
    Umeå University, Umeå, Sweden.
    Taylor, Kimberly E
    Engleman Rheumatology Research Center, San Francisco, California, USA.
    Sandling, Johanna K
    Uppsala University, Uppsala, Sweden.
    Bengtsson, Christine
    Umeå University, Umeå, Sweden.
    Frodlund, Martina
    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.
    Jönsen, Andreas
    Skåne University Hospital, Lund, Sweden.
    Eketjäll, Susanna
    Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden.
    Jensen-Urstad, Kerstin
    Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska Institutet, Karolinska University Hospital, Stockholm, 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.
    Bengtsson, Anders A
    Skåne University Hospital, Lund, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Uppsala, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Uppsala, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Umeå, Sweden.
    Criswell, Lindsey A
    Engleman Rheumatology Research Center, San Francisco, California, USA..
    Rönnblom, Lars
    Uppsala University, Uppsala, Sweden.
    Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis.2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.

    METHODS: Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).

    RESULTS: We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10-5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10-3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10-7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10-5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.

    CONCLUSIONS: The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

  • 44.
    Lewander, Per
    et al.
    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. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Larsson, B.
    Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    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.
    Circulating cartilage oligomeric matrix protein in juvenile idiopathic arthritis2017In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 46, no 3, p. 194-197Article in journal (Refereed)
    Abstract [en]

    Objectives: Raised serum cartilage oligomeric matrix protein (sCOMP) has been reported to predict erosive disease in early rheumatoid arthritis (RA). In juvenile idiopathic arthritis (JIA), subnormal sCOMP levels have been associated with ongoing inflammation and growth retardation. In this study we aimed to assess sCOMP, C-reactive protein (CRP), and insulin-like growth factor (IGF)-1 in children/adolescents with JIA and in referents.Method: We enrolled 52 JIA patients at planned outpatient visits and 54 inpatients with ongoing infection (infection referents). A total of 120 referents testing negative for immunoglobulin (Ig)E-mediated allergy (IgE referents) served as controls. All serum samples were analysed for COMP, IGF-1, and CRP.Results: The average sCOMP level was highest among the IgE referents and lowest among the infection referents. In the JIA patients, the level of sCOMP was not associated with the level of CRP or with clinical signs of disease activity.Conclusions: The results of this study do not support routine clinical analysis of sCOMP levels in patients with JIA.

  • 45.
    Li, He
    et al.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA.
    Ragna Reksten, Tove
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Bergen, Norway.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Wang, Shaofeng
    Oklahoma Medical Research Fdn, OK 73104 USA.
    He, Bo
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Glenn, Stuart B.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miceli-Richard, Corinne
    University of Paris Sud, France.
    Bowman, Simon
    University Hospital Birmingham, England.
    Lester, Sue
    Queen Elizabeth Hospital, Australia.
    Eriksson, Per
    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.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Brun, Johan G.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Goransson, Lasse G.
    Stavanger University Hospital, Norway.
    Harboe, Erna
    Stavanger University Hospital, Norway.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Kvarnstrom, Marika
    Karolinska Institute, Sweden.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Patel, Ketan
    University of Minnesota, MN 55455 USA; North Mem Medical Centre, MN USA.
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Darise Farris, A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Chodosh, James
    Harvard Medical Sch, MA USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN 55455 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Hefner, Kimberly S.
    Cedars Sinai Medical Centre, CA 90048 USA; Hefner Eye Care and Opt Centre, OK USA.
    Houston, Glen D.
    University of Oklahoma, OK USA; Heartland Pathol Consultants, OK USA.
    Huang, Andrew J. W.
    Washington University, MO 63130 USA.
    Hughes, Pamela J.
    University of Minnesota, MN 55455 USA.
    Lewis, David M.
    University of Oklahoma, OK USA.
    Radfar, Lida
    University of Oklahoma, OK USA.
    Vista, Evan S.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Santo Tomas Hospital, Philippines.
    Edgar, Contessa E.
    Oklahoma Baptist University, OK USA.
    Rohrer, Michael D.
    University of Minnesota, MN 55455 USA.
    Stone, Donald U.
    Johns Hopkins University, MD USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Turner, Sean
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Segal, Barbara M.
    University of Minnesota, MN 55455 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Hal Scofield, R.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; US Department Vet Affairs, OK USA.
    Kovats, Susan
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Mariette, Xavier
    University of Paris Sud, France.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Ng, Wan-Fai
    Newcastle University, England; Newcastle University, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Identification of a Sjögrens syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006820Article in journal (Refereed)
    Abstract [en]

    Sjogrens syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2-5-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3 end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  • 46.
    Liu, Ke
    et al.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kurien, Biji T.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA.
    Zimmerman, Sarah L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; Cincinnati VA Medical Centre, OH USA.
    Taft, Diana H.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Lazaro, Sara
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Weaver, Carrie A.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adler, Adam J.
    Oklahoma City VA Medical Centre, OK USA; Oklahoma Medical Research Fdn, OK 73104 USA.
    Chodosh, James
    Massachusetts Eye and Ear Infirm, MA 02114 USA; Harvard University, MA USA.
    Radfar, Lida
    University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Stone, Donald U.
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Lewis, David M.
    University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Li, Shibo
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Koelsch, Kristi A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Igoe, Ann
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Talsania, Mitali
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Kumar, Jay
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Maier-Moore, Jacen S.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA; University of Texas El Paso, TX 79968 USA.
    Harris, Valerie M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN USA.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Lessard, James A.
    Valley Bone and Joint Clin, ND USA.
    Lu, Xianglan
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    -Eric Gottenberg, Jacques
    Strasbourg University, France.
    -Manuel Anaya, Juan
    University of Rosario, Colombia.
    Cunninghame-Graham, Deborah S.
    Kings Coll London, England.
    Huang, Andrew J. W.
    University of Minnesota, MN USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Hughes, Pamela
    University of Minnesota, MN USA.
    Mei, Gabor G.
    MedImmune, MD USA; National Institute Dent and Craniofacial Research, MD USA.
    Miceli-Richard, Corinne
    University of Paris 11, France; INSERM, France.
    Keystone, Edward C.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Bykerk, Vivian P.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Hospital Special Surg, NY 10021 USA; Weill Cornell Med, NY USA.
    Hirschfield, Gideon
    University of Birmingham, England.
    Xie, Gang
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Toronto Gen Hospital, Canada.
    Ng, Wan-Fai
    NIHR Newcastle Biomed Research Centre, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Eriksson, Per
    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. Newcastle University, England.
    Omda, Roald
    Stavanger University Hospital, Norway.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Rohrer, Michael
    University of Minnesota, MN USA.
    Sega, Barbara M.
    University of Minnesota, MN 55455 USA; Hennepin County Medical Centre, MN 55415 USA.
    Vvse, Timothy J.
    Kings Coll London, England.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Pons-Este, Bernardo
    Sanatorio Parque, Argentina.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; Centre Pfizer University of Granada Junta de Andalucia Genom, Spain.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Thompson, Susan D.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Edberg, Jeffrey C.
    University of Alabama Birmingham, AL USA.
    Kimberly, Robert P.
    University of Alabama Birmingham, AL USA.
    Alarcon, Gracicla S.
    University of Alabama Birmingham, AL USA.
    Langefeld, Carl L.
    Wake Forest University, NC 27109 USA.
    Gilkeson, Gary S.
    Medical University of S Carolina, SC USA.
    Kamen, Diane L.
    Medical University of S Carolina, SC USA.
    Tsao, Betty P.
    University of Calif Los Angeles, CA 90095 USA.
    Joseph McCune, W.
    University of Michigan, MI 48109 USA.
    Salmon, Jane E.
    Hospital Special Surg, NY 10021 USA; Weill Cornell Med, NY USA.
    Merrill, Joan T.
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA; University of Calif Los Angeles, CA 90095 USA.
    Utset, Tammy
    University of Chicago, IL 60637 USA.
    Bottinger, Erwin P.
    Mt Sinai Hospital, NY 10029 USA.
    Amos, Christopher I.
    Dartmouth Coll, NH 03755 USA.
    Siminovitch, Katherine A.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Toronto Gen Hospital, Canada.
    Mariette, Xavier
    University of Paris 11, France; INSERM, France.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Harley, John B.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; Cincinnati VA Medical Centre, OH USA.
    Hal Scofield, R.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA.
    X Chromosome Dose and Sex Bias in Autoimmune Diseases2016In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 5, p. 1290-1300Article in journal (Refereed)
    Abstract [en]

    Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

  • 47.
    Maritati, Federica
    et al.
    Parma University Hospital, Italy.
    Fenoglio, Roberta
    G Bosco Hospital, Italy; University of Turin, Italy.
    Pillebout, Evangeline
    St Louis Hospital, France.
    Emmi, Giacomo
    University of Florence, Italy.
    Urban, Maria L.
    Parma University Hospital, Italy.
    Rocco, Rossana
    Parma University Hospital, Italy.
    Nicastro, Maria
    Parma University Hospital, Italy.
    Incerti, Monia
    Parma University Hospital, Italy.
    Goldoni, Matteo
    University of Parma, Italy.
    Trivioli, Giorgio
    Parma University Hospital, Italy.
    Silvestri, Elena
    University of Florence, Italy.
    Mohammad, Aladdin J.
    Lund University, Sweden; University of Cambridge, England.
    Jayne, David
    University of Cambridge, England.
    Eriksson, Per
    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.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Novikov, Pavel
    Sechenov First Moscow State Medical University, Russia.
    Harris, Helen
    Whytemans Brae Hospital, Scotland.
    Roccatello, Dario
    G Bosco Hospital, Italy; University of Turin, Italy.
    Vaglio, Augusto
    Parma University Hospital, Italy.
    Brief Report: Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schonlein)2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 1, p. 109-114Article in journal (Refereed)
    Abstract [en]

    ObjectiveAdult-onset IgA vasculitis (Henoch-Schonlein) (IgAV) is a rare systemic vasculitis characterized by IgA1-dominant deposits. The treatment of adult-onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell-depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody-associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult-onset IgAV. MethodsIn this multicenter observational study, we included patients with adult-onset IgAV who had received RTX either for refractory/relapsing disease or because they had contraindications to conventional glucocorticoid/immunosuppressive therapy. We analyzed the rates of remission (defined on the basis of the Birmingham Vasculitis Activity Score [BVAS]) and relapse as well as the variations over time in estimated glomerular filtration rate (GFR), proteinuria, C-reactive protein (CRP) level, BVAS, and prednisone dose. ResultsTwenty-two patients were included; their median duration of follow-up was 24 months (interquartile range 18-48 months). Sixteen patients received RTX as add-on therapy and 6 as monotherapy. Twenty patients (90.9%) achieved remission, and 7 of those 20 patients (35%) had subsequent relapse of disease. There were significant reductions in 24-hour proteinuria (P amp;lt; 0.0001), CRP level (P = 0.0005), BVAS (P amp;lt; 0.0001), and prednisone dose (P amp;lt; 0.0001) from RTX initiation through the last follow-up visit; estimated GFR remained stable. RTX was generally well tolerated. One patient died after 60 months of follow-up. ConclusionOur data suggest that RTX is an effective and safe therapeutic option for adult-onset IgAV.

  • 48.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Johansson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    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.
    Immunoglobulin (Ig)G1 and IgG4 anti-cyclic citrullinated peptide (CCP) associate with shared epitope, whereas IgG2 anti-CCP associates with smoking in patients with recent-onset rheumatoid arthritis (the Swedish TIRA project).2017In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 188, no 1, p. 53-62Article in journal (Refereed)
    Abstract [en]

    Given the possible importance of anti-citrullinated peptide/protein antibodies (ACPA) for initiation and progression of rheumatoid arthritis (RA), extended knowledge about the different isotypes and subclasses is important. In the present study, we analysed the immunoglobulin (Ig)G subclasses regarding reactivity against cyclic citrullinated peptides (anti-CCP) among 504 clinically well-characterized patients with recent-onset RA in relation to smoking habits, shared epitope (SE) status and IgA and pan-IgG anti-CCP antibodies. All patients, regardless of pan-IgG anti-CCP status, were analysed for IgG1-4 CCP reactivity. Sixty-nine per cent were positive in any IgG anti-CCP subclass, and of these 67% tested positive regarding IgG1, 35% IgG2, 32% IgG3, and 59% IgG4 anti-CCP. Among ever-smokers the percentages of IgG2 anti-CCP (P = 0·01) and IgA anti-CCP (P = 0·002)-positive cases were significantly higher compared to never-smokers. A positive IgG anti-CCP subclass -negative cases. Combining SE and smoking data revealed that IgG1 and IgG4 anti-CCP were the IgG anti-CCP isotypes associated with expression of SE, although the lower number of patients positive for IgG2 or IgG3 anti-CCP could, however, have influenced the results. High levels of IgG2 anti-CCP were shown to correlate with expression of the 'non-SE' allele human leucocyte antigen (HLA)-DRB1*15. In conclusion, in this study we describe different risk factor characteristics across the IgG anti-CCP subclasses, where IgG2 appears similar to IgA anti-CCP regarding the predominant association with smoking, while IgG1 and IgG4 related more distinctly to the carriage of SE genes.

  • 49.
    Mohammad, Aladdin J
    et al.
    Lunds University, Addenbrooke's Hospital Cambridge UK.
    Weiner, Maria
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    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.
    Johansson, Martin E
    Lund University, Malmö .
    Bengtsson, Anders A
    Lund University, Lund .
    Ståhl-Hallengren, Christina
    Helsingborg Hospital .
    Nived, Ola
    Lund University.
    Eriksson, Per
    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.
    Sturfelt, Gunnar
    Lund University.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Health Sciences.
    Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden.2015In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30, p. i23-i30Article in journal (Refereed)
    Abstract [en]

    Objectives :The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden.

    METHODS: In the health care districts surrounding the Skåne University Hospital in Lund [mean population ≥18 years (1997-2008), 188 400] and the University Hospital in Linköping [mean population ≥18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period.

    RESULTS: Eighty-two patients (Lund 44 + Linköping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linköping 14). The annual incidence rate per million inhabitants aged ≥18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020.

    CONCLUSIONS: In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage.

  • 50.
    Mummert, Eckart
    et al.
    Inova Diagnostics, Inc., San Diego, CA, USA.
    Fritzler, Marvin J
    University of Calgary, Calgary, Canada.
    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.
    Bentow, Chelsea
    Inova Diagnostics, Inc., San Diego, CA, USA.
    Mahler, Michael
    Inova Diagnostics, Inc., San Diego, CA, USA.
    The clinical utility of anti-double-stranded DNA antibodies and the challenges of their determination.2018In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 459, p. 11-19Article, review/survey (Refereed)
    Abstract [en]

    Autoantibodies against double-stranded DNA (dsDNA) were first described >60 years ago and although they are still one of the most clinically relevant autoantibodies, test results may be more challenging to interpret compared to other autoantibody tests. They are a serological hallmark of systemic lupus erythematosus (SLE) and are included in both the American College of Rheumatology (ACR) and the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE. Furthermore, anti-dsDNA antibodies (a-dsDNA) have been shown to associate with SLE disease activity and coincide with renal involvement. Given their importance and long history, one might assume that immunological tests for a-dsDNA are standardized and give comparable results. However, even though there has been an international reference standard serum (the WHO Wo/80), different methods for the detection of a-dsDNA and tests from different manufacturers give different results for the same samples. This disparity is due to the diversity of possible antibodies generated to this biochemically complex antigen, which may have different clinical associations. The goal of this review is to summarize the current knowledge regarding the clinical associations with a-dsDNA, highlight challenges in a-dsDNA testing, and elucidate the reasons for discrepant results between methods or manufacturers.

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