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  • 1.
    Agelii, M. Leu
    et al.
    Gothenburg Univ, Sweden.
    Andersson, M. L. E.
    Lund Univ, Sweden; Spenshult Res & Dev Ctr, Sweden.
    Jones, B. L.
    Univ Pittsburgh, PA USA.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Hafstrom, I
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Forslind, K.
    Lund Univ, Sweden; Helsingborgs Hosp, Sweden.
    Gjertsson, I
    Gothenburg Univ, Sweden.
    Disease activity trajectories in rheumatoid arthritis: a tool for prediction of outcome2021In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Objective Predicting treatment response and disease progression in rheumatoid arthritis (RA) remains an elusive endeavour. Identifying subgroups of patients with similar progression is essential for understanding what hinders improvement. However, this cannot be achieved with response criteria based on current versus previous Disease Activity Scores, as they lack the time component. We propose a longitudinal approach that identifies subgroups of patients while capturing their evolution across several clinical outcomes simultaneously (multi-trajectories). Method For exploration, the RA cohort BARFOT (n = 2829) was used to identify 24 month post-diagnosis simultaneous trajectories of 28-joint Disease Activity Score and its components. Measurements were available at inclusion (0), 3, 6, 12, 24, and 60 months. Multi-trajectories were found with latent class growth modelling. For validation, the TIRA-2 cohort (n = 504) was used. Radiographic changes, assessed by the modified Sharp van der Heijde score, were correlated with trajectory membership. Results Three multi-trajectories were identified, with 39.6% of the patients in the lowest and 18.9% in the highest (worst) trajectory. Patients in the worst trajectory had on average eight tender and six swollen joints after 24 months. Radiographic changes at 24 and 60 months were significantly increased from the lowest to the highest trajectory. Conclusion Multi-trajectories constitute a powerful tool for identifying subgroups of RA patients and could be used in future studies searching for predictive biomarkers for disease progression. The evolution and shape of the trajectories in TIRA-2 were very similar to those in BARFOT, even though TIRA-2 is a newer cohort.

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  • 2.
    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.

  • 3. Order onlineBuy this publication >>
    Ahmad, Awais
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Autoantibodies in healthy blood donors, rheumatic and autoimmune liver diseases2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autoimmunity is a common phenomenon where the immune system recognises the body's own tissues. Autoimmunity can lead to disease if tissue damage occurs. Autoimmune diseases affect 5–10% of the global population and in many of these autoantibodies can be detected. The autoantibodies can be detected with several different methods. In this thesis, line immunoassays and fluorescence enzyme immunoassay were used to investigate the presence of autoantibodies in blood donors and various disease groups. Line immunoassays use strips while fluorescence enzyme immunoassay uses wells. The strips and wells are coated with proteins that are allowed to react with serum samples from the patient. In the presence of autoantibodies, either a color change (line immunoassay) or a light reaction (fluorescence enzyme immunoassay) occurs.

    Study I and II: With the EuroLine -Autoimmune Liver Diseases- (IgG) line immunoassay, the presence of autoantibodies associated with autoimmune liver diseases was analysed in blood donors, patients with autoimmune liver diseases and patients with SLE. Autoantibodies could be detected in several blood donors. A very rare autoantibody, anti-LC- 1, was more common in blood donors than in patients with autoimmune liver diseases. Despite the presence of the autoantibodies, no association was seen with abnormal liver values in blood donors or patients with SLE. By raising the cut-off, the number of "false positive" results decreased. However, this could not correct the problem with anti-LC-1, which seems to indicate that there is a problem with the LC-1 antigen so that non-specific reactions are detected. The risk of developing autoimmune liver disease was considered to be low in the SLE patients, as none of these patients developed autoimmune liver disease despite several years of follow-up. Most of the positive findings with the EuroLine immunoassay could not be confirmed with other methods, indicating that this method is very sensitive.

    Study III: With the EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) line immunoassay, the rare autoantibodies anti-Th/To and anti-NOR90 could be detected as frequently in blood donors as in patients with systemic sclerosis. Most of the other autoantibodies were more common in patients with systemic sclerosis compared to blood donors and other disease groups. Some of these autoantibodies were associated with specific clinical manifestations, including renal involvement in patients with SLE. These findings need to be verified.

    Study IV: Autoantibodies that bind the U1-RNP protein (anti-U1-RNP) can be detected in patients with SLE. Patients with anti-U1-RNP can be further analysed for the presence of autoantibodies against the protein RNP 70kDa (anti-RNP70). However, the clinical value of further analysis of anti-RNP70 is uncertain. In this study, fluorescence enzyme immunoassay was used to analyse anti-U1-RNP positive samples for anti-RNP70 to evaluate whether it added anything of clinical value in SLE patients. Presence of anti-U1-RNP was associated with low white blood cell counts and less organ damage. However, analysis of anti-RNP70 in patients with SLE did not add any additional clinical information.

    Conclusion: Euroline -Autoimmune Liver Diseases- (IgG) and EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) are tools that are of value in the diagnosis of autoimmune liver diseases and systemic sclerosis, but the methods have high sensitivity which can lead to false positive results. By raising the cut-off, the risk of this can be reduced. Some rare antibodies were found more frequently in blood donors than in patients with the different disease groups, suggesting potential problems with the antigen source. Subtyping of anti-RNP70 in SLE patients with anti-U1-RNP did not add anything of clinical value.

    List of papers
    1. Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes
    Open this publication in new window or tab >>Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes
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    2021 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 203, no 1, p. 22-31Article in journal (Refereed) Published
    Abstract [en]

    Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjogrens syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2 center dot 9%) and three pSS (2 center dot 6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9 center dot 6%) had PBC-associated autoantibodies, 15 (5 center dot 5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7 center dot 4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7 center dot 4%). The prevalence of SMA (4 center dot 4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8 center dot 1%) had PBC-associated, 12 (10 center dot 8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2021
    Keywords
    autoantibodies; autoimmune hepatitis; primary biliary cholangitis; Sjogrens syndrome; systemic lupus erythematosus
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-170539 (URN)10.1111/cei.13512 (DOI)000573490000001 ()32910463 (PubMedID)2-s2.0-85091690857 (Scopus ID)
    Note

    Funding Agencies|Swedish Rheumatism Association; Region ostergotland (ALF grants); Swedish Society of Medicine; King Gustaf Vs 80-year Anniversary foundation; King Gustaf V and Queen Victorias Freemasons foundation

    Available from: 2020-10-16 Created: 2020-10-16 Last updated: 2024-02-05Bibliographically approved
    2. Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test
    Open this publication in new window or tab >>Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test
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    2022 (English)In: Diagnostics, ISSN 2075-4418, Vol. 12, no 7, article id 1572Article in journal (Refereed) Published
    Abstract [en]

    Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturers recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

    Place, publisher, year, edition, pages
    MDPI, 2022
    Keywords
    autoimmune liver disease; AIH; PBC; PML; Sp100; gp210; AMA-M2; EUROLINE
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:liu:diva-187446 (URN)10.3390/diagnostics12071572 (DOI)000831404600001 ()35885478 (PubMedID)
    Note

    Funding Agencies|Region Ostergotland (ALF grants) [RO932055]

    Available from: 2022-08-23 Created: 2022-08-23 Last updated: 2024-02-05
    3. Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis
    Open this publication in new window or tab >>Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis
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    2022 (English)In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, no 1, article id e000732Article in journal (Refereed) Published
    Abstract [en]

    ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p&lt;0.0001) and associated with Ro52/SSA positivity (p&lt;0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

    Place, publisher, year, edition, pages
    BMJ PUBLISHING GROUP, 2022
    Keywords
    Sjogrens Syndrome; Scleroderma; Systemic; Lupus Erythematosus; Interferon Type I; Autoantibodies
    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:liu:diva-191220 (URN)10.1136/lupus-2022-000732 (DOI)000906026900002 ()36581379 (PubMedID)
    Note

    Funding Agencies|King Gustaf V and Queen Victorias Freemasons Foundation; King Gustaf Vs 80-year Anniversary Foundation; Gustafsson Foundation; Swedish Rheumatism Association, Region OEstergoetland (ALF grants)

    Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2024-02-05
    4. Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus
    Open this publication in new window or tab >>Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus
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    2023 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 12, article id 10398Article in journal (Refereed) Published
    Abstract [en]

    The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjogrens syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p &lt; 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

    Place, publisher, year, edition, pages
    MDPI, 2023
    Keywords
    autoantibodies; mixed connective tissue disease; primary Sjogrens syndrome; small nuclear ribonucleoprotein antibodies; systemic lupus erythematosus
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:liu:diva-196857 (URN)10.3390/ijms241210398 (DOI)001014922500001 ()37373545 (PubMedID)
    Available from: 2023-08-24 Created: 2023-08-24 Last updated: 2024-02-05
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  • 4.
    Allen, K. D.
    et al.
    Univ North Carolina Chapel Hill, NC 27599 USA; Univ North Carolina Chapel Hill, NC 27599 USA; Durham Dept Vet Affairs Hlth Care Syst, NC 27705 USA.
    Huffman, K.
    Univ North Carolina Chapel Hill, NC 27599 USA; Univ North Carolina Chapel Hill, NC 27599 USA.
    Cleveland, R. J.
    Univ North Carolina Chapel Hill, NC 27599 USA; Univ North Carolina Chapel Hill, NC 27599 USA.
    van der Esch, M.
    Amsterdam Univ Appl Sci, Netherlands.
    Abbott, J. H.
    Univ Otago, New Zealand.
    Abbott, Allan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Bennell, K.
    Univ Melbourne, Australia.
    Bowden, J. L.
    Univ Sydney, Australia; Royal North Shore Hosp, Australia.
    Eyles, J.
    Univ Sydney, Australia; Royal North Shore Hosp, Australia.
    Healey, E. L.
    Keele Univ, England.
    Holden, M. A.
    Keele Univ, England.
    Jayakumar, P.
    Univ Texas Austin, TX 78712 USA.
    Koenig, K.
    Univ Texas Austin, TX 78712 USA.
    Lo, G.
    Baylor Coll Med, TX 77030 USA; Michael E DeBakey VA Med Ctr, TX USA.
    Losina, E.
    Harvard Med Sch, MA 02115 USA.
    Miller, K.
    Univ Wisconsin Madison, WI USA.
    Osteras, N.
    Diakonhjemmet Hosp, Norway.
    Pratt, C.
    Royal North Shore Hosp, Australia.
    Quicke, J. G.
    Chancery Exchange, England; Keele Univ, England.
    Sharma, S.
    Univ New South Wales, Australia; Ctr Pain IMPACT, Australia.
    Skou, S. T.
    Univ Southern Denmark, Denmark; Naestved Slagelse Ringsted Hosp, Denmark.
    Tveter, A. T.
    Diakonhjemmet Hosp, Norway.
    Woolf, A.
    Royal Cornwall Hosp, England.
    Yu, S. P.
    Univ Sydney, Australia; Royal North Shore Hosp, Australia.
    Hinman, R. S.
    Univ Melbourne, Australia.
    Evaluating Osteoarthritis Management Programs: outcome domain recommendations from the OARSI Joint Effort Initiative2023In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 31, no 7, p. 954-965Article in journal (Refereed)
    Abstract [en]

    Objective: To develop sets of core and optional recommended domains for describing and evaluating Osteoarthritis Management Programs (OAMPs), with a focus on hip and knee Osteoarthritis (OA). Design: We conducted a 3-round modified Delphi survey involving an international group of researchers, health professionals, health administrators and people with OA. In Round 1, participants ranked the importance of 75 outcome and descriptive domains in five categories: patient impacts, implementation outcomes, and characteristics of the OAMP and its participants and clinicians. Domains ranked as "important" or "essential" by & GE;80% of participants were retained, and participants could suggest addi-tional domains. In Round 2, participants rated their level of agreement that each domain was essential for evaluating OAMPs: 0 = strongly disagree to 10 = strongly agree. A domain was retained if & GE;80% rated it & GE;6. In Round 3, participants rated remaining domains using same scale as in Round 2; a domain was recommended as "core" if & GE;80% of participants rated it & GE;9 and as "optional" if & GE;80% rated it & GE;7. Results: A total of 178 individuals from 26 countries participated; 85 completed all survey rounds. Only one domain, "ability to participate in daily activities", met criteria for a core domain; 25 domains met criteria for an optional recommendation: 8 Patient Impacts, 5 Implementation Outcomes, 5 Participant Characteristics, 3 OAMP Characteristics and 4 Clinician Characteristics. Conclusion: The ability of patients with OA to participate in daily activities should be evaluated in all OAMPs. Teams evaluating OAMPs should consider including domains from the optional recommended set, with representation from all five categories and based on stakeholder priorities in their local context. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

  • 5.
    Almroth, Gabriel
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Lönn, Johanna
    Örebro Universitet, Sweden.
    Uhlin, Fredrik
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Physiology, County Hospital, Kalmar, Sweden.
    Andersson, Bengt Andersson
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Hahn-Zoric, Mirjana
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Sclerostin, TNF-alpha and Interleukin-18 Correlate and are Together with Klotho Related to Other Growth Factors and Cytokines in Haemodialysis Patients2016In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 83, no 1, p. 58-63Article in journal (Refereed)
    Abstract [en]

    Patients with chronic renal failure are known to have renal osteodystrophy (bone disease) and increased calcification of vessels. A new marker of bone disease, sclerostin, the two pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-18 (IL-18), and the fibroblast growth factor-23 (FGF-23) receptor-associated marker Klotho were tested in 84 haemodialysis (HD) patients and in healthy controls. The patients had significantly higher levels of the three former markers than of the controls while Klotho was significantly higher in the controls. Low level, but significant, correlations were observed in the patient group when the levels of these four markers were compared to each other and to those of 5 cytokines and growth factors tested earlier; high-sensitive CRP (hsCRP), interleukin-6 (IL-6), hepatocyte growth factor (HGF), fibroblast growth factor-23 (FGF-23) and soluble urokinase plasminogen activator (suPAR). Ln sclerostin correlated positively to Ln hsTNF-alpha, Ln HGF and Ln suPAR. Ln hsTNF-alpha correlated positively to Ln sclerostin, Ln hsCRP, Ln IL-6, Ln FGF-23, Ln suPAR and Ln IL-18. Ln IL-18 correlated positively to Ln suPAR and Ln TNF-alpha. Ln Klotho correlated negatively to Ln hsCRP but did not correlate to Ln FGF-23. The markers studied here may be involved in the calcification of vessels seen in HD patients due to a combination of inflammation and bone disease. The mechanisms are still not fully known but may be of importance for future therapeutic possibilities in this group of patients.

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  • 6.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Spanish Natl Inst Agr & Food Res & Technol INIA CS, Spain.
    Martinez Serrano, Cristina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Spanish Natl Inst Agr & Food Res & Technol INIA CS, Spain.
    Gardela, Jaume
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Ctr Recerca Sanitat Anim CReSA, Spain.
    Nieto, Helena
    Spanish Natl Inst Agr & Food Res & Technol INIA CS, Spain.
    de Mercado, Eduardo
    Spanish Natl Inst Agr & Food Res & Technol INIA CS, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    MicroRNA expression in specific segments of the pig periovulatory internal genital tract is differentially regulated by semen or by seminal plasma2024In: Research in Veterinary Science, ISSN 0034-5288, E-ISSN 1532-2661, Vol. 168, article id 105134Article in journal (Refereed)
    Abstract [en]

    microRNAs play pivotal roles during mammalian reproduction, including the cross-talk between gametes, embryos and the maternal genital tract. Mating induces changes in the expression of mRNA transcripts in the female, but whether miRNAs are involved remains to be elucidated. In the current study, we mapped 181 miRNAs in the porcine peri-ovulatory female reproductive tract: Cervix (Cvx), distal and proximal uterus (Dist-Ut, ProxUt), Utero-tubal-junction (UTJ), isthmus (Isth), ampulla (Amp), and infundibulum (Inf) when exposed to semen (natural mating (NM) or artificial insemination (AI-P1)) or to infusions of sperm-free seminal plasma (SP): the first 10 mL of the sperm rich fraction (SP-P1) or the entire ejaculate (SP-E). Among the most interesting findings, NM decreased mir-671, implicated in uterine development and pregnancy loss prior to embryo implantation, in Cvx, Dist-UT, Prox-UT, Isth, and Inf, while it increased in Amp. NM and SP-E induced the downregulation of miRlet7A-1 (Dist-UT, Prox-UT), a regulator of immunity during pregnancy. miR-34C-1, a regulator of endometrial receptivity gene expression, was increased in Dist-UT, UTJ and Amp (NM), in Prox-UT (AI-P1), and in Amp (SPP1). miR-296, a modulator of the inflammatory response and apoptosis, was upregulated in the UTJ (all treatments). NM elicited the highest miRNA activity in the sperm reservoir (UTJ), suggesting that key-regulators such as miR-34c or miR-296 may modulate the metabolic processes linked to the adequate preparation for gamete encounter in the oviduct. Our results suggest that SP should be maintained in AI to warrant miRNA regulation within the female genital tract for reproductive success.

  • 7.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Univ Autonoma Barcelona, Spain.
    Martinez Serrano, Cristina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Roca, Jordi
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    mRNA expression of oxidative-reductive proteins in boars with documented different fertility can identify relevant prognostic biomarkers2021In: Research in Veterinary Science, ISSN 0034-5288, E-ISSN 1532-2661, Vol. 141, p. 195-202Article in journal (Refereed)
    Abstract [en]

    Oxidative stress unbalance is a major factor causing impairment of sperm function and, ultimately, sperm death. In this study, we identified transcriptomic and proteomic markers for oxidative-related protectors from the generation of reactive oxygen species (ROS) in spermatozoa from breeding boars with documented high- or lowfertility. Particular attention was paid to glutathione peroxidases, and to transcripts related to DNA stabilization and compaction, as protamine and transition proteins. mRNA cargo analysis was performed using porcinespecific micro-arrays (GeneChip (R) miRNA 4.0 and GeneChip (R) Porcine Gene 1.0 ST) and qPCR validation. Differences between fertility-classed boars were ample among biomarkers; some upregulated only at protein level (catalase (CAT), superoxide dismutase 1 (SOD1) and glutathione proteins), or only at the mRNA level (ATOX1, Antioxidant Protein 1). In addition, protamines 2 and 3, essential for sperm DNA condensation and also transition proteins 1 and 2 (TNP1 and TNP2), required during histone-to-protamine replacement, were overexpressed in spermatozoa from high-fertile boars. This up-regulation seems concerted to reduce DNA accessibility to ROS attack, protecting the DNA. The upregulated intracellular phospholipid hydroperoxide glutathione peroxidase (GPx4), in high-fertile boars at mRNA level, can be considered a most relevant biomarker for fertility disclosure during sperm evaluation.

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  • 8.
    Andersson, Bengt-Åke
    et al.
    Jonkoping Univ, Sweden.
    Nilsson, Mats
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Oliva, Delmy
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Impact of single nucleotide polymorphisms and cigarette smoking on cancer risk and survival of patients with head and neck squamous cell carcinoma2022In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 27, no 7, p. 694-700Article in journal (Refereed)
    Abstract [en]

    Background: Head and neck squamous cell carcinoma (HNSCC) is a disease involving genetic and lifestyle risk factors such as smoking or high-risk papillomavirus (HR-HPV) infections. Objective: This study analyzed 92 single nucleotide polymorphisms (SNPs) associated with smoking and HPV on HNSCC cancer risk and survival among HNSCC patients. Material and methods: Eighty-six HNSCC patients (48 non-smoking and 38 smoking) were consecutively included. Results: Differences were detected in the analysis of survival and SNP genotypes located in the CXCR2 and COMT. Five SNPs in genes PRKDC, TGFb, XRCC1, Cyp2A6 and CTLA4 were found to be different when comparing SNP genotypes in all patients and all controls as a risk of HNSCC. When comparing SNP genotypes among smoking patients and smoking controls, six SNPs in the genes PFR1, IL10, CCL4, IL6, Ku70, and PRF1 were detected. When comparing SNP genotypes, nine SNPs in CHRNA3, PRKDC, CHARNA5, IFN-gamma, ESR1, XRCC1, Cyp2A6, CTLA4, and COMT were different in non-smoking patients and non-smoking controls. No association was found between SNP distribution or patient survival and the impact of HR-HPV. Conclusions: The SNPs differed between smokers and non-smokers and could indicate a possible interaction between genetics and smoking. This could play an important role in a better understanding of the pathogenesis of HNSCC.

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  • 9.
    Andersson, Bengt-Åke
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Sayardoust, Shariel
    Inst Postgrad Dent Educ, Sweden.
    Lofgren, Sture
    Ryhov Cty Hosp, Sweden.
    Rutqvist, Lars Erik
    Swedish Match AB, Sweden.
    Lewin, Nongnit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Cigarette smoking affects microRNAs and inflammatory biomarkers in healthy individuals and an association to single nucleotide polymorphisms is indicated2019In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 24, no 2, p. 180-185Article in journal (Refereed)
    Abstract [en]

    Background: Cigarette smoke induces inflammation and remodels immune response. Genetic and epigenetic alterations might be involved in the pathogenesis of smoking related diseases. In this study, we investigated the effect of smoking on systemic inflammation biomarkers and epigenetic changes at microRNA (miRNA) expression level. We also examined if the levels of inflammatory biomarkers were associated with selected single nucleotide polymorphisms (SNPs). Method: From 39 smokers and 101 non-smokers, levels of total white blood cells (WBCs) and its subpopulations, plasma cytokines/chemokines/proteins and miRNAs were analysed. For three biomarkers, C-reactive protein (CRP), MCP-1 and IFN-gamma that were affected by smoking, the influence of SNPs was analyzed. Result: Elevated levels of total WBCs, neutrophils, monocytes, lymphocytes, CRP, MCP-1, IFN-gamma and lower levels of miR-21 were detected in smokers. The elevated levels of IFN-gamma in smokers was only statistically significantly associated with rs2069705 AG/GG SNP-genotype. Conclusions: A lower level of oncomir miRNA-21 and a higher level of immune modelling cytokine IFN-gamma detected in smokers could be a protective immune response to cigarette smoke. The higher level of IFN-gamma in smokers with a specific SNP genotype also suggests that a genetic interaction with smoking might predict the pathobiology of smoking related disease.

  • 10.
    Andersson, Siv Folkhammar
    et al.
    Unit of Rehabilitation, Kalmar County Council, Oskarshamn, Sweden.
    Bergman, Stefan
    Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden; Primary Health Care Unit, Department of Public Health and Community Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Henriksson Welin, Elisabet
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Divison of Nursing, Department of Neurobiology, Care Sciences and Society,Karolinska Institutet, Huddinge, Sweden.
    Bremander, Ann
    Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden; School of Business, Engineering and Science, Halmstad University, Halmstad, Sweden.
    Arthritis management in primary care: A study of physiotherapists current practice, educational needs and adherence to national guidelines2017In: Musculoskeletal Care, ISSN 1478-2189, E-ISSN 1557-0681, Vol. 15, no 4, p. 333-340Article in journal (Refereed)
    Abstract [en]

    Background

    With an increasing number of patients with osteoarthritis (OA) and rheumatoid arthritis (RA) in primary care, our aim was to investigate arthritis‐related practice in physiotherapy and to study adherence to evidence‐based care.

    Methods

    Seventy physiotherapists (PTs) working in primary care were emailed a questionnaire to investigate current practice and the number of roles assumed by PTs, the degree of confidence, educational needs and adherence to national guidelines in managing patients with OA or RA. Interventions supported by national guidelines were compared with reports of treatment modalities in the questionnaire.

    Results

    Sixty‐four (91%) PTs responded, and they reported a higher degree of confidence in assessment, treatment and education of patients with OA than for those with RA (p < 0.001). The total number of roles assumed by the PTs was higher in the management of OA than for RA (p < 0.001). PTs who assumed a greater number of roles also reported a stronger degree of confidence in assessing OA (p = 0.036). Those who assumed fewer roles also reported less confidence in RA treatment (p = 0.045). Recommendations in the guidelines were followed by the majority of PTs for eight of 11 treatment modalities in OA and for six of six in RA.

    Conclusions

    PTs reported a lower degree of confidence and the assumption of fewer roles in managing patients with RA compared with OA. There was good adherence to the national guidelines for almost all the treatment modalities listed. Even so, the results indicate a need for education, especially in chronic inflammatory arthritis care.

  • 11.
    Andraos, Rama
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Ahmad, Awais
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hesselstrand, Roger
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Andreasson, Kristofer
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis2022In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, no 1, article id e000732Article in journal (Refereed)
    Abstract [en]

    ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p&lt;0.0001) and associated with Ro52/SSA positivity (p&lt;0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

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  • 12.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. 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.
    Knopf, Jasmin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Bilyy, Rostyslav
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv Natl Med Univ, Ukraine.
    Vovk, Volodymyr
    Danylo Halytsky Lviv Natl Med Univ, Ukraine.
    Sundgren, Pia C.
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, 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.
    Munoz, Luis E.
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Herrmann, Martin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Höög, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. 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.
    Active NET formation in Libman-Sacks endocarditis without antiphospholipid antibodies: A dramatic onset of systemic lupus erythematosus2018In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 51, no 6, p. 310-318Article in journal (Refereed)
    Abstract [en]

    Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p=.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r=0.65, p=.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.

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  • 13.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Puli, Srinivasulu
    Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Hellmark, Thomas
    Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Pochard, Pierre
    LBAI, UMR1227, Univ Brest, Inserm, CHU de Brest, Brest, France.
    Pers, Jacques-Olivier
    LBAI, UMR1227, Univ Brest, Inserm, Brest, France.
    Ernerudh, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Medicine Center, Department of Nephrology. Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction2023In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 213, no 2, p. 190-201Article in journal (Refereed)
    Abstract [en]

    Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γproduction (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γwas also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the British Society for Immunology.

  • 14.
    Arkema, Elizabeth V
    et al.
    Clinical 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, 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.

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  • 15.
    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.

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  • 16.
    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)
  • 17.
    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.

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  • 18.
    Arkema, Elizabeth V. V.
    et al.
    Karolinska Inst, Sweden.
    Saleh, Muna Atallah
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Simard, Julia F. F.
    Karolinska Inst, Sweden; Stanford Univ, CA USA.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Epidemiology and Damage Accrual of Systemic Lupus Erythematosus in Central Sweden: A Single-Center Population-Based Cohort Study Over 14 Years From ostergotland County2023In: ACR OPEN RHEUMATOLOGY, ISSN 2578-5745, Vol. 5, no 8, p. 426-432Article in journal (Refereed)
    Abstract [en]

    ObjectiveVariations in prevalence and incidence of systemic lupus erythematosus (SLE) within a geographically defined area of central Sweden over a time period of 14 years were examined. Longitudinal differences in disease activity, laboratory test results, and damage accrual were investigated. MethodsAdults (aged & GE;18 years) residing in ostergotland County between 2008 and 2021 (mean adult population: 357,000 citizens) with confirmed SLE were identified and followed prospectively until death, December 31, 2021, or emigration. We estimated annual incidence per 100,000 inhabitants stratified by sex and age. Linear regression with year of diagnosis as the outcome assessed whether each clinical measurement at diagnosis varied over time. ResultsPrevalence on December 31, 2021, was 71.5 of 100,000 (87% female). One hundred twenty-six new cases were identified during the study period, yielding a mean annual incidence of 3.0 of 100,000 inhabitants; this was higher in females (4.8/100,000) than in males (1.2/100,000). Mean age at diagnosis was 43.7 years (SD 17.3). Age at diagnosis and disease activity measures increased over the calendar year of diagnosis (P &lt; 0.05) whereas disease manifestations, including lupus nephritis, did not vary significantly. Accrual of organ damage was demonstrated over time since diagnosis and stratified by sex, lupus nephritis, and corticosteroid-related damage. Approximately 40% developed damage within 5 years. ConclusionSLE prevalence and incidence estimates remained constant over 14 years, and disease phenotypes at SLE onset were similar. SLE was diagnosed also among older individuals with a smaller female-to-male ratio. Estimates of prevalence and incidence were comparable to previous Scandinavian reports but lower than observed in registry data from the US and the UK.

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  • 19.
    Askling, J
    et al.
    Karolinska University Hospital, Stockholm, Sweden.
    Baecklund, E
    Uppsala University Hospital, Uppsala, Sweden.
    Granath, F
    Karolinska University Hospital, Stockholm, Sweden.
    Geborek, P
    Lund University Hospital, Lund, Sweden.
    Fored, M
    Karolinska University Hospital, Stockholm, Sweden.
    Backlin, C
    Uppsala University, Uppsala, Sweden.
    Bertilsson, L
    Sahlgrens University Hospital, Gothenburg, Sweden.
    Cöster, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Jacobsson, L T
    Malmö University Hospital, Malmö, Sweden.
    Lindblad, S
    Karolinska University Hospital, Stockholm, Sweden.
    Lysholm, J
    Falu County Hospital, Falun, Sweden.
    Rantapaa-Dahlqvist, S
    Umeå University Hospital, Umeå, Sweden.
    Saxne, T
    University of Lund Hospital, Lund, Sweden.
    van Vollenhoven, R
    Karolinska University Hospital, Stockholm, Sweden.
    Klareskog, L
    Karolinska University Hospital, Stockholm, Sweden.
    Feltelius, N
    Medical Products Agency, Uppsala, Sweden.
    Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register2009In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 5, p. 648-653Article in journal (Refereed)
    Abstract [en]

    Background: Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis ( RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern.

    Methods: Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67 743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 ( n = 6604) were identified. A general population comparator ( n = 471 024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals.

    Results: Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26 981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients ( 336 lymphomas during 365 026 person-years) and 2.72 ( 95% CI 1.82 to 4.08) versus the general population comparator ( 1568 lymphomas during 3 355 849 person-years). RA patients starting anti-TNF therapy in 1998-2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent.

    Conclusion: Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.

  • 20.
    Barbulescu, Andrei
    et al.
    Karolinska Inst, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindstrom, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 10, p. 3952-3962Article in journal (Refereed)
    Abstract [en]

    Objectives To describe the use of baricitinib and tofacitinib by Swedish RA patients and to compare their effectiveness with that of biologic DMARDs (bDMARDs). Methods RA patients who initiated baricitinib (n = 1420), tofacitinib (n = 316), abatacept (n = 1050), IL-6 inhibitors (IL-6is; n = 849), rituximab (n = 1101) or TNF inhibitors (TNFis; n = 6036) between January 2017 and November 2019 were followed for a minimum of 1 year using data from several linked Swedish national registers. Proportions reaching a good EULAR 28-joint DAS (DAS28) response, HAQ Disability Index (HAQ-DI) improvement &gt;0.2 units and Clinical Disease Activity Index (CDAI) remission were compared at 1 year, imputing discontinued treatments as non-response. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to 3 months after treatment initiation. Results On average, baricitinib, and particularly tofacitinib, were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted 1 year response proportions were consistently lower on TNFi compared with baricitinib, with differences of -4.3 percentage points (95% CI -8.7, 0.1) for good EULAR response, -9.9 (-14.4 to -5.4) for HAQ-DI improvement and -6.0 (-9.8 to -2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to 3 months supported the 1 year findings. Conclusions Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures.

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  • 21.
    Barranco, Isabel
    et al.
    Univ Murcia, Spain; Univ Girona, Spain.
    Tvarijonaviciute, Asta
    Univ Murcia, Spain.
    Padilla, Lorena
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Roca, Jordi
    Univ Murcia, Spain.
    Lucas, Xiomara
    Univ Murcia, Spain.
    Delays in processing and storage of pig seminal plasma alters levels of contained antioxidants2021In: Research in Veterinary Science, ISSN 0034-5288, E-ISSN 1532-2661, Vol. 135, p. 416-423Article in journal (Refereed)
    Abstract [en]

    Seminal plasma (SP) antioxidants are considered biomarkers of sperm function and fertility for AI-boars. The current protocol for their measurement implies the SP was harvested immediately after ejaculation and prompt stored at -80 degrees C until analysis. Such protocol may be impractical for AI-centers. This study evaluated how SP levels of antioxidants were influenced by delays in (1) SP-harvesting (0 [control], 2 or 24 h at 17 degrees C after ejaculate collection), in (2) SP-freezing (0 [control] or 24 hat 17 degrees C after SP-harvesting) or (3) the temperature of storage (-80 degrees C [control] or - 20 degrees C). The SP-antioxidants evaluated were: glutathione peroxidase [GPx], superoxide dismutase [SOD], paraoxonase-1 [PON-1], trolox equivalent antioxidant capacity [TEAC] and oxidative stress index [OSI]. A total of 120 aliquots from 10 entire ejaculates were handled in three trials. They were centrifuged (1500 g, 10 min) for harvesting SP and antioxidants were measured with an Automatic Chemistry Analyzer. A 24 h-delay in harvesting the SP led to an increase (p 0.001) in TEAC and SOD SP-levels, and a decrease (p 0.05) of OSI and PON-1. Similarly, a 24 h-delay to freeze the SP increased (p 0.01) TEAC values and decreased (p 0.01) PON-1 and GPx activity levels. Finally, storing the SP at -20 degrees C decreased (p 0.001) SP-levels of TEAC, PON-1 and GPx, and increased (p 0.01) OSI values. Strong positive relationships (p 0.001) were found between antioxidant SP-levels in processed samples and their respective controls. In sum, handling and SP storage influence antioxidant measurements in AI-boars. Reliable levels of SP-antioxidants can only be warranted if a strict protocol for harvesting and SP storage is followed.

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  • 22.
    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.

  • 23.
    Berglin, Ewa
    et al.
    Umea Univ, Sweden.
    Mohammad, Aladdin J.
    Lund Univ, Sweden; Univ Cambridge, England.
    Dahlqvist, Johanna
    Uppsala Univ, Sweden.
    Johansson, Linda
    Umea Univ, Sweden.
    Eriksson, Catharina
    Umea Univ, Sweden.
    Sjöwall, Johanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis: A case-control study2021In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 117, article id 102579Article in journal (Refereed)
    Abstract [en]

    Objectives: Anti-neutrophil cytoplasmic autoantibodies [ANCA) are important for diagnosis of ANCA-associated vasculitides (AAV). The timing of antibody development is not well established. To investigate the development of proteinase 3 (PR3)and myeloperoxidase (MPO)-ANCA, blood samples collected before onset of symptoms of AAV were analysed. Methods: To identify AAV patients with blood samples predating symptoms, the National Patient Register and Cause of Death register were scrutinized for ICD codes for AAV and linked to the registers of five biobanks. Diagnoses of AAV and time point for symptom onset were confirmed by reviewing 504 case-record. Eighty-five AAV cases (34 males, 51 females) with samples 1 month &lt; 10 years from AAV symptom onset and two controls matched for sex, age, and sampling time for each case were included. Samples were screened using ELISAs for ANCA and further analysed for PR3-or MPO- specificities. Results: In ANCA-screen 35.7% of the pre-symptomatic cases and 3.5% of controls tested positive (p &lt; 0.01). 26.2% of the cases were PR3-ANCA+ and 10.7% MPO-ANCA+. Median (Q1-Q3) predating time for PR3-ANCA+ was 2.7 (0.3-7.7) years and MPO-ANCA+ 2.0 (0.9-3.5) years. PR3-ANCA was demonstrated in samples up to nine years before symptom onset. At symptom onset predating PR3-ANCA+ cases were younger than PR3-ANCA(P &lt; 0.01), and MPO-ANCA+ were older than MPO-ANCA(p &lt; 0.05). Predating MPO-ANCA+ cases vs. MPO ANCAand vs. PR3-ANCA+ cases had more often at symptoms onset manifestations from lungs, kidneys or peripheral nervous system (p &lt; 0.01 and p &lt; 0.05, respectively). Conclusion: The PR3-and MPO-ANCAs are present years before AAV symptom onset and represent distinct diseases.

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  • 24.
    Bjorvatn Saevik, Ase
    et al.
    Univ Bergen, Norway.
    Akerman, Anna-Karin
    Orebro Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Methlie, Paal
    Univ Bergen, Norway; Haukeland Hosp, Norway.
    Quinkler, Marcus
    Endocrinol Charlottenburg, Germany.
    Palmström Jorgensen, Anders
    Oslo Univ Hosp, Norway.
    Hoybye, Charlotte
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Debowska, Aleksandra J.
    Vestfold Hosp Trust, Norway.
    Nedrebo, Bjorn Gunnar
    Univ Bergen, Norway; Haugesund Hosp, Norway.
    Dahle, Anne Lise
    Haugesund Hosp, Norway.
    Carlsen, Siri
    Stavanger Univ Hosp, Norway.
    Tomkowicz, Aneta
    Sorlandet Hosp, Norway.
    Sollid, Stina Therese
    Vestre Viken Hlth Trust, Norway.
    Nermoen, Ingrid
    Akershus Univ Hosp, Norway.
    Gronning, Kaja
    Akershus Univ Hosp, Norway.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Grimnes, Guri
    Univ Hosp North Norway, Norway; UiT Arctic Univ Norway, Norway.
    Skov, Jakob
    Karolinska Inst, Sweden.
    Finnes, Trine
    Innlandet Hosp Trust, Norway.
    Valland, Susanna F.
    Innlandet Hosp Trust, Norway.
    Wahlberg, Jeanette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Holte, Synnove Emblem
    Sorlandet Hosp, Norway.
    Simunkova, Katerina
    Univ Bergen, Norway.
    Kampe, Olle
    Univ Bergen, Norway; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Husebye, Eystein Sverre
    Univ Bergen, Norway; Haukeland Hosp, Norway; Karolinska Inst, Sweden.
    Bensing, Sophie
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Oksnes, Marianne
    Univ Bergen, Norway; Haukeland Hosp, Norway; Karolinska Inst, Sweden.
    Residual Corticosteroid Production in Autoimmune Addison Disease2020In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 105, no 7, p. 2430-2441Article in journal (Refereed)
    Abstract [en]

    Context

    Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis.

    Objective

    To determine frequencies and clinical features of residual corticosteroid production in patients with AAD.

    Design

    Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test.

    Results

    Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = –0.487; P < 0.001).

    Conclusion

    In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.

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  • 25. Order onlineBuy this publication >>
    Björk, Mathilda
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences.
    Aspects of Disability in Rheumatoid Arthritis: a five-year follow-up in the Swedish TIRA project2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rheumatoid arthritis (RA) is a progressive disease, often leading to disability. Because the disease course develops rapidly during the first years after diagnosis, more knowledge is needed about the early disease course to minimize later disability. This thesis describes the course of disability in early RA such as hand function, pain intensity, activity limitation and sick leave. In addition, this thesis compares disability between women and men and compares disability between RA patients and referents.

    This thesis is primarily based on data from the 320 patients that were included in the multi-centre project in Sweden called ‘Early interventions in rheumatoid arthritis’ (TIRA). A wide range of outcome variables was registered between 1996 and 2006 during regular follow-ups from time for diagnosis through the eight-year follow-up. Outcome regarding disease activity and disability of RA patients still remaining in TIRA at the three and five year follow-up respectively are used in this thesis. Data concerning sick leave were obtained for the patients during six years (1993-2001) – three years before and three years after diagnosis. Referents were included in two of the studies. Data regarding disability in referents were obtained according to hand function and activity limitation using the Health Assessment Questionnaire (HAQ). Data for sick leave were obtained for six years in referents, for the same period as the RA patients.

    For most variables, disability in RA was most pronounced at time of diagnosis but before intervention started. Disability was then reduced already at the 3-month follow-up and thereafter affected but stable during the following five years. The exception was participation, reflected by sick leave, a variable that was stable from inclusion to three years from diagnosis. Activity limitation, pain intensity and sick leave in RA that represents different aspects of disability were explained by other aspects of disability and contextual factors rather than by disease activity. RA affects women and men differently in some aspects. Women had more severe course of activity limitations than men according to HAQ. Men were more affected than women in range of motion, although the differences were small in a clinical perspective. However, pain intensity and frequency of sick leave did not differ between women and men. Patients with RA have pronounced disability in relation to referents although several variables improve soon after diagnosis. This discrepancy refers to hand function as well as activity limitations and sick leave. The frequency of sick leave increased during the year before diagnosis in relation to referents and was thereafter high compared to sick leave in referents.

    List of papers
    1. Hand function in women and men with early rheumatoid arthritis: A prospective study over three years (the Swedish TIRA project)
    Open this publication in new window or tab >>Hand function in women and men with early rheumatoid arthritis: A prospective study over three years (the Swedish TIRA project)
    2006 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 35, no 1, p. 15-19Article in journal (Refereed) Published
    Abstract [en]

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

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

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

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

    Place, publisher, year, edition, pages
    Informa Healthcare, 2006
    Keywords
    Hand function, course, sex differences, rheumatoid arthritis, impairment, assessment
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13327 (URN)10.1080/03009740510026562 (DOI)000235183300003 ()
    Available from: 2008-06-02 Created: 2008-06-02 Last updated: 2017-12-13Bibliographically approved
    2. Hand Function and Activity Limitation According to Health Assessment Questionnaire in Patients with Rheumatoid Arthritis and Healthy Referents: 5-Year Followup of Predictors of Activity Limitation (The Swedish TIRA Project)
    Open this publication in new window or tab >>Hand Function and Activity Limitation According to Health Assessment Questionnaire in Patients with Rheumatoid Arthritis and Healthy Referents: 5-Year Followup of Predictors of Activity Limitation (The Swedish TIRA Project)
    2007 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 34, no 2, p. 296-302Article in journal (Refereed) Published
    Abstract [en]

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

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

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

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

    Place, publisher, year, edition, pages
    Toronto, Ontario, Canada: Journal of Rheumatology Publishing Co. Ltd., 2007
    Keywords
    Rheumatoid Arthritis, Disabilty, Longitudinal studies, Sex differences, Reference values
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13328 (URN)000244112900012 ()
    Available from: 2008-06-02 Created: 2008-06-02 Last updated: 2017-12-13Bibliographically approved
    3. Multivariate relationships between pain intensity and other aspects of health in rheumatoid arthritis: cross sectional and five year longitudinal analyses (the Swedish TIRA project)
    Open this publication in new window or tab >>Multivariate relationships between pain intensity and other aspects of health in rheumatoid arthritis: cross sectional and five year longitudinal analyses (the Swedish TIRA project)
    2008 (English)In: Disability and Rehabilitation, ISSN 0963-8288, Vol. 30, no 19, p. 1429-1438Article in journal (Refereed) Published
    Abstract [en]

    Objectives: This study analyses the relationships between pain intensity and other aspects of health commonly used to assess disease activity and disability in early rheumatoid arthritis and examines whether such relationships were different between women and men.

    Subjects and methods: This study included the 189 patients (69% women) with early RA (symptoms <12 months at diagnosis) still remaining in the Swedish TIRA cohort 5 years after inclusion. Disease activity and disability was assessed 3, 6, 12, 18, 24, 36, 48, and 60 months (M0-M60) after inclusion by erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), number of swollen and tender joints, physicians global assessment of disease activity (PGA), grip force average over 10 seconds (Grippit), Grip Ability Test (GAT), Signals of Functional Impairment (SOFI) in hand, lower limb and upper limb, Health Assessment Questionnaire (HAQ), and pain intensity measured with a visual analogue scale (VAS). The variables were divided into meaningful blocks according to the correlation structure in a principal component analysis (PCA) at M60. Using hierarchical partial least squares (PLS) analyses, this study investigated the blocks cross-sectionally to test for correlations with pain intensity at M0 and M60. The blocks at M0 were also used as predictors of pain intensity at M60 in a hierarchical PLS.

    Results: The strongest relationship was found between pain intensity and the second block, consisting of HAQ and SOFI-lower limb at the cross-sectional analyses in both women and men. The block representing disease activity (i.e., ESR, CRP, PGA, and swollen and tender joints) had the weakest relation to pain intensity. According to the longitudinal analyses, the disease activity variables (block 1) at M0 had the strongest relationship to pain intensity at M60 in men. In contrast, HAQ and SOFI-lower limb (block 2) at M0 had a strong relation to pain intensity in women.

    Keywords
    pain intensity, predictions, principal component analysis, prospective study, Rheumatoid arthritis, sex differences, pain, research, longitudinal method
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13329 (URN)10.1080/09638280701623356 (DOI)
    Available from: 2008-06-02 Created: 2008-06-02 Last updated: 2013-09-13
    4. Sick leave before and after diagnosis of rheumatoid arthritis in relation to referens: A report from the Swedish TIRA project
    Open this publication in new window or tab >>Sick leave before and after diagnosis of rheumatoid arthritis in relation to referens: A report from the Swedish TIRA project
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    2009 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 36, no 6, p. 1170-1179Article in journal (Refereed) Published
    Abstract [en]

    Objective. Our study describes sick leave during 3 years before and 3 years after diagnosis of rheumatoid arthritis (RA) in relation to referents and identifies predictors for sick leave during the third year after diagnosis of RA.

    Methods. One hundred twenty patients (76% women) from the Swedish early RA study TIRA were included. Disease activity and disability were registered regularly during 3 years in TIRA. Referents were matched for sex, age, and home town. Sick leave data were obtained for patients 3 years before and 3 years after diagnosis and for the referents for the corresponding 6 years.

    Results. No differences were seen between patients and referents regarding sick leave during the first 2 years, whereas sick leave increased in patients 6 months before diagnosis, from 30% to 53%. During the 3 years after diagnosis, sick leave among patients was rather stable, varying between 50% and 60%, even though disability pension increased and sickness benefit decreased. Sick leave before diagnosis, disability 1 year after diagnosis, and type of work were identified as predictors for sick leave during the third year after diagnosis.

    Conclusion. Not surprisingly, sick leave in patients increased the year before diagnosis. Although disease activity and disability diminished after diagnosis, the patients’ sick leave remained essentially unchanged. Sick leave 3 years after diagnosis was foremost predicted by earlier sick leave, disability, and type of work.

    Place, publisher, year, edition, pages
    Journal of Rheumatology Publishing Co. Ltd., 2009
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13330 (URN)10.3899/jrheum.080523 (DOI)000266891500016 ()
    Available from: 2008-06-02 Created: 2008-06-02 Last updated: 2017-12-13Bibliographically approved
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  • 26.
    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 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.

  • 27.
    Björk Wilhelms, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cyclooxygenase isoform exchange blocks inflammatory symptoms2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

  • 28.
    Bolin, Karin
    et al.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Imgenberg-Kreuz, Juliana
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Pucholt, Pascal
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Haarhaus, Malena Loberg
    Karolinska Univ Hosp Stockholm, Sweden.
    Almlöf, Jonas Carlsson
    Uppsala Univ, Sweden.
    Nititham, Joanne
    Univ Calif San Francisco, CA 94132 USA.
    Jönsen, Andreas
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp Stockholm, Sweden.
    Syvänen, Ann-Christine
    Uppsala Univ, Sweden.
    Lerang, Karoline
    Univ Oslo, Norway.
    Troldborg, Anne
    Aarhus Univ Hosp, Denmark; Aarhus Univ, Denmark.
    Voss, Anne
    Odense Univ Hosp, Denmark.
    Molberg, Öyvind
    Univ Oslo, Norway.
    Jacobsen, Sören
    Copenhagen Univ Hosp, Denmark.
    Criswell, Lindsey
    Univ Calif San Francisco, CA 94132 USA.
    Rönnblom, Lars
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Variants in BANK1 are associated with lupus nephritis of European ancestry2021In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 22, p. 194-202Article in journal (Refereed)
    Abstract [en]

    The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p &lt; 1 x 10(-4), NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 x 10(-4)) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 x 10(-7)). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.

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  • 29.
    Boonen, Annelies
    et al.
    Division of Rheumatology, Maastricht University Medical Centre+ Internal Medicine, Maastricht, The Netherlands; Universiteit Maastricht Care and Public Health Research Institute, Maastricht, The Netherlands.
    Putrik, Polina
    Division of Rheumatology, Maastricht University Medical Centre+ Internal Medicine, Maastricht, The Netherlands; Universiteit Maastricht Care and Public Health Research Institute, Maastricht, The Netherlands.
    Marques, Mary Lucy
    Rheumatologist, Leiden University Medical Center, Leiden, The Netherlands; Rheumatology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.
    Alunno, Alessia
    Rheumatology Unit, University of Perugia Department of Medicine, Perugia, Italy.
    Abasolo, Lydia
    Department of Rheumatology, Instituto de Investigation Sanitaria San Carlos, Hospital Clinico Universitario San Carlos, Madrid, Spain.
    Beaton, Dorcas
    Mobility Program Clinical Research Unit, St Michael's Hospital Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada.
    Betteridge, Neil
    Neil Betteridge Associates, London, UK.
    Björk, Mathilda
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Boers, Maarten
    Department of Epidemiology and Data Science; Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, Amsterdam, The Netherlands.
    Boteva, Boryana
    Patients with Arthritis and Rheumatism (PARE) working group, European League Against Rheumatism, Zurich, Switzerland.
    Fautrel, Bruno
    PEPITES teams, Pierre Louis Institute for Epidemiology and Public Health, Inserm UMR 1136, Paris, France; Rheumatology Dept, Pitié Salpetriere Hospital, Sorbonne University; Assistance Publique- Hôpitaux de Paris, Paris, Fance.
    Guillemin, Francis
    APEMAC, Université de Lorraine, Nancy, France; CIC Epidémiologie Clinique, CHRU Nancy, Inserm, Université de Lorraine, Nancy, France.
    Mateus, Elsa F
    Portuguese League Against Rheumatic Diseases (LPCDR) and Comprehensive Health Research Centre (CHRC), Lisbon, Portugal; People with Arthritis and Rheumatism (PARE), European League Against Rheumatism, Zurich, Switzerland.
    Nikiphorou, Elena
    Centre for Rheumatic Diseases, King’s College of London, London, UK; Rheumatology Department, King’s College Hospital, London, UK.
    Péntek, Márta
    Health Economics Research Center, University Research and Innovation Center, Óbuda University, Budapest, Hungary.
    Pimentel Santos, Fernando
    Rheumatology Department, Centro Hospitalar de Lisboa Ocidental EPE Hospital de Egas Moniz, Lisboa, Portugal; NOVA Medical School, Lisboa, Portugal.
    Severens, Johannes L
    Erasmus School of Health Policy & Management and iMTA, Institute for Medical Technology Assessment, Erasmus University Rotterdam, Rotterdam, The Netherlands.
    Verstappen, Suzanne M M
    Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, UK.
    Walker-Bone, Karen
    MRC Versus Arthritis Centre for Musculoskeletal Health and Work, MRC Life course Epidemiology Unit, Southampton General Hospital, Southampton, UK.
    Wallman, Johan Karlsson
    Department of Clinical sciences, Lund University, Lund, Sweden; Department of Rheumatology, Skåne University Hospital, Lund, Sweden.
    Ter Wee, Marieke M
    Department of Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Rheumatology and immunology, AI&I, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Westhovens, René
    Dept of Rheumatology, KU Leuven University Hospitals Leuven, Leuven, Belgium; Skeletal Biology and Engineering Research Centre, KU Leuven Department of Development and Regeneration, Leuven, Belgium.
    Ramiro, Sofia
    Rheumatology, Leiden University Medical Center, Leiden, The Netherlands; Rheumatology, Zuyderland Medical Centre Heerlen, Heerlen, The Netherlands.
    EULAR Points to Consider (PtC) for designing, analysing and reporting of studies with work participation as an outcome domain in patients with inflammatory arthritis2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 9, p. 1116-1123, article id annrheumdis-2020-219523Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Clinical studies with work participation (WP) as an outcome domain pose particular methodological challenges that hamper interpretation, comparison between studies and meta-analyses.

    OBJECTIVES: To develop Points to Consider (PtC) for design, analysis and reporting of studies of patients with inflammatory arthritis that include WP as a primary or secondary outcome domain.

    METHODS: The EULAR Standardised Operating Procedures were followed. A multidisciplinary taskforce with 22 experts including patients with rheumatic diseases, from 10 EULAR countries and Canada, identified methodologic areas of concern. Two systematic literature reviews (SLR) appraised the methodology across these areas. In parallel, two surveys among professional societies and experts outside the taskforce sought for additional methodological areas or existing conducting/reporting recommendations. The taskforce formulated the PtC after presentation of the SLRs and survey results, and discussion. Consensus was obtained through informal voting, with levels of agreement obtained anonymously.

    RESULTS: Two overarching principles and nine PtC were formulated. The taskforce recommends to align the work-related study objective to the design, duration, and outcome domains/measurement instruments of the study (PtC: 1-3); to identify contextual factors upfront and account for them in analyses (PtC: 4); to account for interdependence of different work outcome domains and for changes in work status over time (PtC: 5-7); to present results as means as well as proportions of patients reaching predefined meaningful categories (PtC: 8) and to explicitly report volumes of productivity loss when costs are an outcome (PtC:9).

    CONCLUSION: Adherence to these EULAR PtC will improve the methodological quality of studies evaluating WP.

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  • 30.
    Bower, Hannah
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    di Giuseppe, Daniela
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Ahlenius, Gerd-Marfie
    Umea Univ, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Feltelius, Nils
    Swedish Med Prod Agcy, Sweden; Uppsala Univ, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Klareskog, Lars
    Karolinska Inst, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Lindstrom, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Askling, Johan
    Karolinska Inst, Sweden.
    Effects of the COVID-19 pandemic on patients with inflammatory joint diseases in Sweden: from infection severity to impact on care provision2021In: RMD Open, E-ISSN 2056-5933, Vol. 7, no 3, article id e001987Article in journal (Refereed)
    Abstract [en]

    Objectives To compare risks for COVID-19-related outcomes in inflammatory joint diseases (IJDs) and across disease-modifying antirheumatic drugs (DMARDs) during the first two waves of the pandemic and to assess effects of the pandemic on rheumatology care provision. Methods Through nationwide multiregister linkages and cohort study design, we defined IJD and DMARD use annually in 2015-2020. We assessed absolute and relative risks of hospitalisation or death listing COVID-19. We also assessed the incidence of IJD and among individuals with IJD, rheumatologist visits, DMARD use and incidence of selected comorbidities. Results Based on 115 317 patients with IJD in 2020, crude risks of hospitalisation and death listing COVID-19 (0.94% and 0.33% across both waves, respectively) were similar during both waves (adjusted HR versus the general population 1.33, 95% CI 1.23 to 1.43, for hospitalisation listing COVID-19; 1.23, 95% CI 1.08 to 1.40 for death listing COVID-19). Overall, biological disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) did not increase risks of COVID-19 related hospitalisation (with the exception of a potential signal for JAK inhibitors) or death. During the pandemic, decreases were observed for IJD incidence (-7%), visits to rheumatology units (-16%), DMARD dispensations (+6.5% for bDMARD/tsDMARDs and -8.5% for conventional synthetic DMARDs compared with previous years) and for new comorbid conditions, but several of these changes were part of underlying secular trends. Conclusions Patients with IJD are at increased risk of serious COVID-19 outcomes, which may partially be explained by medical conditions other than IJD per se. The SARS-CoV-2 pandemic has exerted measurable effects on aspects of rheumatology care provision demonstrated, the future impact of which will need to be assessed.

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  • 31.
    Bower, Hannah
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Di Giuseppe, Daniela
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Ahlenius, Gerd-Marie
    Umea Univ, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Feltelius, Nils
    Swedish Med Prod Agcy, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Klareskog, Lars
    Karolinska Inst, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Lindström, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Askling, Johan
    Karolinska Inst, Sweden.
    Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population: a nationwide Swedish cohort study2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 8, p. 1086-1093Article in journal (Refereed)
    Abstract [en]

    Objectives To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies. Methods Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression. Results During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited. Conclusions Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks.

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  • 32.
    Brolin, Sara
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Welin, Elisabet
    Orebro Univ, Sweden.
    Lövström, Björn
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Nephrology. Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pettersson, Susanne
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Exploring the educational needs of patients with systemic vasculitis using the educational needs assessment tool2022In: Rheumatology: Advances in Practice, E-ISSN 2514-1775, Vol. 6, no 2, article id rkac062Article in journal (Refereed)
    Abstract [en]

    Lay Summary What does this mean for patients? ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease, with high morbidity if left untreated. Patients who receive education on their disease increase their ability to self-monitor potential symptoms. They can recognize early signs and symptoms of relapse, stay compliant with treatment more easily, achieve long-term positive outcomes and prevent increased morbidity. Patients with AAV who are educated regarding medications and potential side effects also report better health-related quality of life. To investigate what type of education is needed among these patients, we used a questionnaire that measures educational needs, the educational needs assessment tool (ENAT). Our aim was to investigate the educational needs in AAV patients with ENAT and to explore whether it differs related to sex, age, education, diagnosis, disease duration and disease activity. The ENAT questionnaire has been used previously in other rheumatic diseases, but not in AAV. We found that 38% of our patients with AAV desired more education, especially on the disease process, self-management and treatment. Women and those with shorter disease duration expressed a greater need for education than men and those with longer disease duration. The ENAT questionnaire has proved useful to help tailor educational efforts for patients with AAV. Objectives Knowledge and health literacy enable patients to monitor symptoms and disease impact. Educational needs have previously been explored in rheumatology, but scarcely for patients with ANCA-associated vasculitis (AAV). The aim of the study was to assess the educational needs among patients with AAV using the educational needs assessment tool (ENAT). Methods This was a cross-sectional observational study including adults with AAV. Educational needs were captured by ENAT. Total ENAT (0-117 points, with higher numbers indicating higher educational need) and the seven domains (managing pain, movement, feelings, disease process, treatment, self-management and support systems) were explored regarding sex, age, education, diagnosis, disease duration and disease activity. To compare domains, a percentage response (0-100%) was calculated. Results One hundred and seventy-eight individuals (50% men; 34% with disease duration &lt;= 2 years) were included. The total ENAT mean was 66.5 (s.d. 26.6; 57%), with domains as follows: disease process, 78%; self-management, 69%; treatments, 64%; feelings, 56%; managing pain, 48%; support systems, 47%; and movement, 41%. Higher educational needs were found among women in the domains movement, feelings and disease process and in total ENAT (all P &lt; 0.04) compared with men. Higher educational needs were also seen in patients with disease duration &lt;= 2 years regarding disease process, self-management and support systems and in total ENAT compared with patients with longer disease duration (all P &lt; 0.03). Conclusion This study revealed great educational needs among AAV patients. Some groups expressed higher needs (women and those with shorter disease duration). Increased education for patients with AAV might lead to improved self-care and treatment adherence.

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  • 33.
    Bureychak, Tetyana
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Olsen Faresjö, Åshild
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Sjödahl, Jenny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Norlin, Anna-Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Mantorp.
    Walter, Susanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Symptoms and health experience in irritable bowel syndrome with focus on men2022In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 34, no 11, article id e14430Article in journal (Refereed)
    Abstract [en]

    Background Irritable bowel syndrome (IBS) is a disorder with a predominance in women; IBS in men is less studied. The present study evaluated symptoms as well as health and social experiences of men with IBS. Methods This cross-sectional study included 293 patients with IBS (64 men) and 363 non-IBS controls (62 men). Gastrointestinal symptom diaries were filled in prospectively, and data on comorbidities and healthcare-seeking behavior were assessed by questionnaires. Men with IBS were compared with men without IBS and women with IBS. Key results Compared with women with IBS, men with IBS had fewer contacts with the healthcare system, fewer psychiatric comorbidities, fewer sleeping problems, and less chronic pain. Urgency to defecate and nausea were less common, and stool frequency was higher in men with IBS. There was no difference between men with and without IBS in terms of educational level, satisfaction with household economy, or living with a partner. In contrast, women with IBS more often lived alone, were more often dissatisfied with household economy, and had a lower educational level than women without IBS. Men with IBS had the same proportion of full-time employment as men without IBS but in contrast, the proportion of women with IBS in full-time employment was only 34%, compared to 50% of the women without IBS. Conclusion and inferences The present study improves the understanding of mens experiences of IBS and suggests that sex and gender may be integrated into the biopsychosocial model of IBS.

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  • 34.
    Bybrant, Mara Cerqueiro
    et al.
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Grahnquist, Lena
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Ortqvist, Eva
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Pediatric Diabetes Clinic, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Andersson, Cecilia
    Department of clinical sciences, Lund University, Skåne University hospital, Malmö, Sweden.
    Forsander, Gun
    The Queen Silvia Children’s hospital, Sahlgrenska University hospital and The Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Elding Larsson, Helena
    Department of clinical sciences, Lund University, Skåne University hospital, Malmö, Sweden.
    Lernmark, Ake
    Department of clinical sciences, Lund University, Skåne University hospital, Malmö, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Marcus, Claude
    Division of Pediatrics, Department of Clinical Science, Intervention and Technology Karolinska Institutet, Stockholm, Sweden.
    Carlsson, Annelie
    Department of Pediatrics, Lund University, Lund, Sweden.
    Ivarsson, Sten A.
    Department of clinical sciences, Lund University, Skåne University hospital, Malmö, Sweden.
    Tissue transglutaminase autoantibodies in children with newly diagnosed type 1 diabetes are related to human leukocyte antigen but not to islet autoantibodies: A Swedish nationwide prospective population-based cohort study2018In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 51, no 5, p. 221-227Article in journal (Refereed)
    Abstract [en]

    Objectives: This study explored the association between tissue transglutaminase autoantibody (tTGA), high-risk human leucocyte antigen (HLA) genotypes and islet autoantibodies in children with newly diagnosed type 1 diabetes (T1D).

    Patients and methods: Dried blood spots and serum samples were taken at diagnosis from children <18 years of age participating in Better Diabetes Diagnosis (BDD), a Swedish nationwide prospective cohort study of children newly diagnosed with T1D. We analyzed tTGA, high-risk HLA DQ2 and DQ8 (DQX is neither DQ2 nor DQ8) and islet auto-antibodies (GADA, IA-2A, IAA, and three variants of Zinc transporter; ZnT8W, ZnT8R, and ZnT8QA).

    Results: Out of 2705 children diagnosed with T1D, 85 (3.1%) had positive tTGA and 63 (2.3%) had borderline values. The prevalence of tTGA was higher in children with the HLA genotypes DQ2/2, DQ2/X or DQ2/8 compared to those with DQ8/8 or DQ8/X (p = .00001) and those with DQX/X (p ≤ .00001). No significant differences were found in relation to islet autoantibodies or age at diagnosis, but the presence of tTGA was more common in girls than in boys (p = .018).

    Conclusion: tTGA at T1D diagnosis (both positive and borderline values 5.4%) was higher in girls and in children homozygous for DQ2/2, followed by children heterozygous for DQ2. Only children with DQ2 and/or DQ8 had tTGA. HLA typing at the diagnosis of T1D can help to identify those without risk for CD.

  • 35.
    Bäckryd, Emmanuel
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Themistocleous, Andreas
    Univ Oxford, England.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Gordh, Torsten
    Uppsala Univ, Sweden.
    Rice, Andrew S. C.
    Imperial Coll London, England.
    Tesfaye, Solomon
    Sheffield Teaching Hosp NHS Fdn Trust, England.
    Bennett, David L.
    Univ Oxford, England.
    Gerdle, Björn
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Hepatocyte growth factor, colony-stimulating factor 1, CD40, and 11 other inflammation-related proteins are associated with pain in diabetic neuropathy: exploration and replication serum data from the Pain in Neuropathy Study2022In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 163, no 5, p. 897-909Article in journal (Refereed)
    Abstract [en]

    One in 5 patients with diabetes suffers from chronic pain with neuropathic characteristics, but the pathophysiological mechanisms underlying the development of neuropathic pain in patients with diabetic distal symmetrical polyneuropathy (DSP) are poorly understood. Systemic low-grade inflammation has been implicated, but there is still a considerable knowledge gap concerning its scope and meaning in this context. The aim of the study was to establish the broad inflammatory signature of painful diabetic DSP in serum samples from the Pain in Neuropathy Study, an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the present two cohorts exploration-replication study (180 participants in each cohort), serum samples from Pain in Neuropathy Study participants were analyzed with the Olink INFLAMMATION panel (Olink Bioscience, Uppsala, Sweden) that enables the simultaneous measurement of 92 inflammation-related proteins (mainly cytokines, chemokines, and growth factors). In both the exploration and the replication cohort, we identified a high-inflammation subgroup where 14 inflammation-related proteins in particular were associated with more neuropathy and higher pain intensity. The top 3 proteins were hepatocyte growth factor, colony-stimulating factor 1, and CD40 in both cohorts. In the exploratory cohort, additional clinical data were available, showing an association of inflammation with insomnia and self-reported psychological distress. Hence, this cross-sectional exploration-replication study seems to confirm that low-grade systemic inflammation is related to the severity of neuropathy and neuropathic pain in a subgroup of patients with diabetic DSP. The pathophysiological relevance of these proteins for the development of neuropathic pain in patients with diabetic DSP must be explored in more depth in future studies.

  • 36.
    Cao, Shan
    et al.
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Shanghai Jiao Tong Univ, Peoples R China.
    Li, Yixuan
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Shanghai Jiao Tong Univ, Peoples R China.
    Song, Rui
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Shanghai Jiao Tong Univ, Peoples R China.
    Meng, Xianyi
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Fuchs, Maximilian
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Fraunhofer Inst Toxicol & Expt Med, Germany.
    Liang, Chunguang
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Wurzburg Hubland, Germany.
    Kachler, Katerina
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Meng, Xinyu
    Shanghai Jiao Tong Univ, Peoples R China.
    Wen, Jinming
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Sun Yat sen Univ, Peoples R China.
    Schloetzer-Schrehardt, Ursula
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Taudte, Verena
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Philipps Univ Marburg, Germany.
    Gessner, Arne
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Kunz, Meik
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Fraunhofer Inst Toxicol & Expt Med, Germany.
    Schleicher, Ulrike
    Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Zaiss, Mario M.
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Chen, Xiaoxiang
    Shanghai Jiao Tong Univ, Peoples R China.
    Schett, Georg
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Bozec, Aline
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    L-arginine metabolism inhibits arthritis and inflammatory bone loss2023In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060Article in journal (Refereed)
    Abstract [en]

    ObjectivesTo investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss.MethodsL-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by mu CT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients.ResultsL-arginine inhibited arthritis and bone loss in all three models and directly blocked TNF alpha-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients.ConclusionOur study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.

  • 37.
    Casal Moura, Marta
    et al.
    Mayo Clin Coll Med & Sci, MN USA; Univ Porto, Portugal.
    Gauckler, Philipp
    Med Univ Innsbruck, Austria.
    Anders, Hans-Joachim
    Hosp Ludwig Maximilians Univ, Germany.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Fernandez-Juarez, Gema M.
    Hosp Univ La Paz, Spain.
    Floege, Juergen
    RWTH Aachen Univ Hosp, Germany.
    Frangou, Eleni
    Limassol Gen Hosp, Cyprus; Univ Nicosia, Cyprus.
    Goumenos, Dimitrios
    Patras Univ Hosp, Greece.
    Segelmark, Marten
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Turkmen, Kultigin
    Necmettin Erbakan Univ, Turkiye.
    van Kooten, Cees
    Leiden Univ, Netherlands.
    Tesar, Vladimir
    Charles Univ Prague, Czech Republic.
    Geetha, Duvuru
    Johns Hopkins Univ, MD USA.
    Fervenza, Fernando C.
    Mayo Clin, MN USA.
    Jayne, David R. W.
    Univ Cambridge, England.
    Stevens, Kate I
    Queen Elizabeth Univ Hosp, Scotland.
    Kronbichler, Andreas
    Univ Cambridge, England.
    ERA Immunonephrol Working Grp IWG,
    Management of antineutrophil cytoplasmic antibody-associated vasculitis with glomerulonephritis as proposed by the ACR 2021, EULAR 2022 and KDIGO 2021 guidelines/recommendations2023In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 38, no 11, p. 2637-2651Article, review/survey (Refereed)
    Abstract [en]

    Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past 10 years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids and avacopan, and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates.

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  • 38. Order onlineBuy this publication >>
    Chalise, Jaya Prakash
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Immune tolerance by interferon-alpha in experimental arthritis2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type I Interferons (mainly IFN-α & IFN-β) belong to a family of cytokines that possess strong antiviral and immunomodulatory properties. Pro- and/or anti-inflammatory effects of type I IFN have been observed in infectious diseases and several autoimmune diseases including SLE, MS, RA and experimental models thereof, but what defines either outcome is largely obscure. The main aim of this thesis is to understand how IFN-α may act anti-inflammatory in a model of antigen-induced arthritis (AIA). In this model, mice are sensitised with methylated-BSA (mBSA) emulsified in Freund’s adjuvant at day 1 and 7 followed by intra-articular injection of mBSA in the knee joint at day 21, which induces arthritis within 1 week.

    Administration of IFN-α at the time of mBSA sensitisations (day 1 and day 7) but not at induction of arthritis (day 21) clearly protected against arthritis in a type I IFN receptor dependent manner. Humoral immunity might not be involved in this protection as the levels of antigen-specific IgG (total, IgG1, IgG2a and IgG2b), IgA, IgE in serum were not altered in IFN-α treated mice. However, IFN-α-protection was accompanied by delayed and decreased antigen-specific proliferative responses in spleen and lymph node cells ex vivo, including impaired proliferative recall responses after intra-articular antigenic challenge.

    In the course of AIA, IFN-α inhibited the increase of circulatory IL-6, IL-10, IL-12, and TNF in the sensitisation phase (day 0-21) and also the re-call response of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 induced by intra-articular mBSA challenge in arthritis phase (day 21-28). This IFN-α-inhibition of cytokines was also apparent in mBSA-re-stimulated spleen and lymph node cell cultures ex vivo, including inhibited cytokine production in CD4+ T helper cells and macrophages. In contrast to the inhibition of pro-inflammatory cytokines, the levels of immunomodulatory TGF-β was clearly enhanced in IFN-α-treated mice, both in serum and in re-stimulated leucocytes cultures including both macrophages, especially in the sensitisation phase, and in CD4+ T cells in the arthritis phase. By  inhibiting TGF-β signalling in vivo, the protective effect of IFN-α was  shown to be dependent on TGF-β signalling in the sensitisation phase.

    The cytokine TGF-β is an activator of the indoleamine 2,3 dioxygnese (IDO1), a potent immuneregulatory component that acts via enzymatic production of kynurenine (Kyn) and signalling activity. The IFN-α-protective effect in AIA was associated with both increased expression and enzymatic activity of IDO1 and the IFN-α-protection was totally ablated in mice lacking IDO1 expression (IDO1 KO mice) and in mice treated with the inhibitor of the enzymatic activity of IDO1 (1-Methyl Tryptophan; 1-MT). Interestingly, administration of the IDO-metabolite Kyn protected mice from AIA in an IFNARindependent manner. These observations show that the IDO1 enzymatic activity is important for the protective effect of IFN-α. Using 1-MT, it was further shown that the enzymatic activity of IDO1 was, like TGF-β, crucial only at the sensitisation but not in the arthritis phase of AIA for IFN-α to protect against arthritis. Instead, IDO1’s non-enzymatic signalling activity, characterized by sustained expression of IDO1 and non-canonical NF-κB activation in pDCs, was observed in the arthritis phase in spleen cells from mice treated with IFN-α.

    Regulatory T cells (Treg cells) were also found to be important for IFN-α-protection in AIA. Transient depletion of Treg cells by diphtheria toxin in DEREG mice in the arthritis phase, but not during the sensitisation phase abolished IFN-α-protection. Treatment with IFN-α enhanced the numbers of Treg cells in the course of AIA and their function; compared to untreated mice, Treg cells isolated at day 10 and 20 of AIA from IFN-α- treated mice exhibited higher suppressive activity against mBSA-stimulated proliferation of responder T cells. The enhancing effect of IFN-α on Treg cell numbers was observed in blood, spleen, LNs and also in ex-vivo cultures of leucocytes re-stimulated with mBSA and IFN-α. Although IFN-α clearly increased the suppressive activity of Treg cells, adoptive transfer of Treg cells from mBSA immunized mice, regardless of IFN-α treatment, prevented the development of arthritis.

    Conclusion

    In the presence of IFN-α during antigen sensitisation, a state of tolerance is established, which is able to prevent joint inflammation induced by antigenic re-challenge. This immunological tolerance is created in the sensitisation phase of AIA and is characterized by inhibition of pro-inflammatory cytokines, increased TGF-β production and activity of the IDO1 enzyme, the latter two being indispensable for IFN-α-induced protection. Administration of Kyn, the metabolite of the enzymatic activity of IDO1, in the sensitisation phase also protected against AIA downstream of type I IFN signalling. In the arthritis phase regulatory T cells, whose numbers and suppressive capacity was clearly enhanced by IFN-α, mediate the actual prevention of arthritis development in IFN-α-treated animals. We have thus identified molecular and cellular components of the anti-inflammatory program elicited by IFN-α including Kyn that may not have the pro-inflammatory effects associated with IFN.

    List of papers
    1. Type I IFN protects against antigen-induced arthritis
    Open this publication in new window or tab >>Type I IFN protects against antigen-induced arthritis
    2011 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 6, p. 1687-1695Article in journal (Refereed) Published
    Abstract [en]

    Autoimmune diseases including rheumatoid arthritis (RA) involve immune reactions against specific antigens. The type I IFN system is suspected to promote autoimmunity in systemic lupus erythematosus, but may also dampen immune reactions in e. g. inflammatory bowel disease. This prompted us to investigate the role of type I IFN in antigen-induced arthritis (AIA). The importance of type I IFN in methylated (m) BSA-induced arthritis was studied by using mice deficient for the type I IFN receptor (IFNAR) and by administration of the IFN-alpha activator viral double-stranded (ds) RNA or recombinant IFN-alpha at antigen sensitization. In IFNAR knock-out mice, arthritis severity was significantly higher than in WT mice. Administration of dsRNA at antigen sensitization protected WT but not IFNAR KO mice from arthritis. Also, addition of recombinant IFN-alpha during the immunization, but not the induction phase of arthritis, almost abolished arthritis. Protection mediated by IFN-alpha was accompanied by delayed and decreased antigen-specific proliferative responses, including impaired lymph node recall responses after intra-articular antigenic challenge. In conclusion, we demonstrate that type I IFN can prevent joint inflammation by downregulating antigen-specific cellular immunity.

    Place, publisher, year, edition, pages
    John Wiley and Sons, Ltd, 2011
    Keywords
    Arthritis; Tolerance; Type I IFN
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-69898 (URN)10.1002/eji.201040956 (DOI)000291559700019 ()
    Available from: 2011-08-09 Created: 2011-08-08 Last updated: 2017-12-08
    2. Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis
    Open this publication in new window or tab >>Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis
    2013 (English)In: Arthritis Research and Therapy, ISSN 1478-6354, Vol. 15, no 5, p. R143-Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Interferon alpha (IFN-α) has a complex role in autoimmunity, in that it may both enhance and prevent inflammation. We have previously shown that the presence of IFN-α at sensitization protects against subsequent antigen-triggered arthritis. To understand this tolerogenic mechanism, we performed a descriptive, hypothesis-generating study of cellular and humoral responses associated with IFN-α-mediated protection against arthritis.Methods: Arthritis was evaluated at day 28 in mice given a subcutaneous injection of methylated bovine serum albumin (mBSA), together with Freund adjuvant and 0 to 5,000 U IFN-α at days 1 and 7, followed by intraarticular injection of mBSA alone at day 21. The effect of IFN-α on mBSA-specific IgG1, IgG2a, IgG2b, IgA, and IgE was evaluated by enzyme-linked immunosorbent assay (ELISA). Cytokines in circulation and in ex vivo cultures on mBSA restimulation was evaluated with ELISA and Luminex, and the identity of cytokine-producing cells by fluorescence-activated cell sorting (FACS) analysis.Results: Administration of IFN-α protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-α did inhibit the initial increase of IL-6, IL-10, IL-12, and TNF, and the recall response induced by intraarticular mBSA challenge of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 in serum. IFN-α decreased both macrophage and CD4+ T cell-derived IFN-γ production, whereas IL-17 was decreased only in CD4+ T cells. Ex vivo, in mBSA-restimulated spleen and lymph node cell cultures, the inhibitory effect of in vivo administration of IFN-α on proinflammatory cytokine production was clearly apparent, but had a time limit. An earlier macrophage-derived, and stronger activation of the antiinflammatory cytokine transforming growth factor beta (TGF-β) was observed in IFN-α-treated animals, combined with an increase in CD4+ T cells producing TGF-β when arthritis was triggered by mBSA (day 21). Presence of IFN-α at immunizations also prevented the reduction in TGF-β production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.Conclusions: Administration of IFN-α has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-α at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-β production, first in macrophages, and later also in CD4+ T cells. On intraarticular antigen challenge, this antiinflammatory state is reenforced, manifested as inhibition of proinflammatory recall responses and preservation of TGF-β levels. This may explain why IFN-α protects against antigen-induced arthritis. © 2013 Chalise et al.; licensee BioMed Central Ltd.

    Place, publisher, year, edition, pages
    London, UK: BioMed Central, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102367 (URN)10.1186/ar4326 (DOI)000329737400043 ()
    Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2015-11-03Bibliographically approved
    3. IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritis
    Open this publication in new window or tab >>IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Interferon-α (IFN-α) prevents antigen-induced arthritis (AIA) in mice by an unknown mechanism. Indoleamine 2, 3 dioxygenase 1 (IDO1) is an immunoregulator via enzymatic as well as signalling activity, which can be activated by TGF-β and further mediated via non canonical NF-κB signalling. We here investigated whether IDO1 and TGF-β are involved in IFN-α protective effects in AIA. Arthritis was induced in wt, Ido1-/- or Ifnar-/- mice, treated or not with IFN-α or kynurenine, the main IDO1 product, and antibodies neutralizing TGF-β or 1-methyltryptophan (1-MT), an inhibitor of IDO1 catalytic activity. IDO1 expression and enzymatic activity were determined by RT-PCR and HPLC, respectively. Proliferation was measured by 3H-Thymidine incorporation. Non-canonical NF-κB signalling was evaluated by ELISA and Western blot in plasmacytoid DCs (pDCs) from treated mice. Protective effects of IFN-α in AIA were associated with increased IDO1 expression and kynurenine production in spleen cells, particularly at the time of mBSA sensitization. Lack of IDO1 ablated IFN-α protection and kynurenine prevented AIA in an IFNAR-independent manner. The IDO1 catalytic activity was crucial for IFN-α effects at the sensitization but not effector phase of AIA. The disease effector phase in mice treated with IFN-α was instead characterized by sustained IDO1 and TGF-β expression and activation of the noncanonical NF-κB pathway in pDCs. IFN-α protective effects in AIA involves IDO1 enzymatic and signalling activity in the disease sensitization and effector phase, respectively. Kynurenine, the main IDO1 metabolite, can be used as an alternative treatment to IFN-α in protecting mice from AIA.

    National Category
    Pharmacology and Toxicology Rheumatology and Autoimmunity Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-122461 (URN)
    Funder
    Swedish Research CouncilSwedish Rheumatism AssociationLinköpings universitet
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-01-10Bibliographically approved
    4. Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritis
    Open this publication in new window or tab >>Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritis
    Show others...
    (English)Manuscript (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.

    Keywords
    Interferon alpha, regulatory T cells, antigen induced arthritis, TGF-beta
    National Category
    Pharmacology and Toxicology Rheumatology and Autoimmunity Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-122462 (URN)
    Funder
    Swedish Research CouncilSwedish Rheumatism AssociationLinköpings universitet
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-01-10Bibliographically approved
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  • 39.
    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.

  • 40.
    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.
    Pallotta, Maria Teresa
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    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.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Iacono, Alberta
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Boon, Louis
    EPIRUS Biopharmaceuticals, Utrecht, Netherlands.
    Grohmann, Ursula
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritisManuscript (preprint) (Other academic)
    Abstract [en]

    Interferon-α (IFN-α) prevents antigen-induced arthritis (AIA) in mice by an unknown mechanism. Indoleamine 2, 3 dioxygenase 1 (IDO1) is an immunoregulator via enzymatic as well as signalling activity, which can be activated by TGF-β and further mediated via non canonical NF-κB signalling. We here investigated whether IDO1 and TGF-β are involved in IFN-α protective effects in AIA. Arthritis was induced in wt, Ido1-/- or Ifnar-/- mice, treated or not with IFN-α or kynurenine, the main IDO1 product, and antibodies neutralizing TGF-β or 1-methyltryptophan (1-MT), an inhibitor of IDO1 catalytic activity. IDO1 expression and enzymatic activity were determined by RT-PCR and HPLC, respectively. Proliferation was measured by 3H-Thymidine incorporation. Non-canonical NF-κB signalling was evaluated by ELISA and Western blot in plasmacytoid DCs (pDCs) from treated mice. Protective effects of IFN-α in AIA were associated with increased IDO1 expression and kynurenine production in spleen cells, particularly at the time of mBSA sensitization. Lack of IDO1 ablated IFN-α protection and kynurenine prevented AIA in an IFNAR-independent manner. The IDO1 catalytic activity was crucial for IFN-α effects at the sensitization but not effector phase of AIA. The disease effector phase in mice treated with IFN-α was instead characterized by sustained IDO1 and TGF-β expression and activation of the noncanonical NF-κB pathway in pDCs. IFN-α protective effects in AIA involves IDO1 enzymatic and signalling activity in the disease sensitization and effector phase, respectively. Kynurenine, the main IDO1 metabolite, can be used as an alternative treatment to IFN-α in protecting mice from AIA.

  • 41. Order onlineBuy this publication >>
    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.
    Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.

    Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.

    Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

    List of papers
    1. Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
    Open this publication in new window or tab >>Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
    2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 10, p. e0141863-Article in journal (Refereed) Published
    Abstract [en]

    Objective Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. Methods Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice preimmunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. Results Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. Conclusion Local, but not systemic administration of uridine efficiently prevented development of antigen- induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2015
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-123070 (URN)10.1371/journal.pone.0141863 (DOI)000363920300089 ()26512984 (PubMedID)
    Note

    Funding Agencies|Vetenskapsradet-Grant [521-2011-3095]; Reumatikerforbundet Grant [155261]; County Council of Ostergotland, Sweden; Linkoping University

    Available from: 2015-12-04 Created: 2015-12-03 Last updated: 2021-06-14
    2. IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
    Open this publication in new window or tab >>IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
    Show others...
    2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, no 8, p. 3142-3151Article in journal (Refereed) Published
    Abstract [en]

    IFN-alpha prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-beta signaling for this anti-inflammatory property of IFN-alpha. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1(-/-), or Ifnar(-/-) mice, treated or not with IFN-alpha or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-beta, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-beta and pDC, respectively. IDO1 expression was determined by RT-PCR, Western blot, and FACS, and enzymatic activity by HPLC. Proliferation was measured by H-3-thymidine incorporation and TGF-beta by RT-PCR and ELISA. WT but not Ido1(-/-) mice were protected from AIA by IFN-alpha, and Kyn, the main IDO1 product, also prevented AIA, both in WTand Ifnar(-/-) mice. Protective treatment with IFN-alpha increased the expression of IDO1 in pDC during AIA, and Ab-mediated depletion of pDC, either during mBSA sensitization or after triggering of arthritis, completely abrogated the protective effect of IFN-alpha. IFN-alpha treatment also increased the enzymatic IDO1 activity (Kyn/tryptophan ratio), which in turn activated production of TGF-beta. Neutralization of enzymatic IDO1 activity or TGF-beta signaling blocked the protective effect of IFN-alpha against AIA, but only during sensitization and not after triggering of arthritis. Likewise, inhibition of the IDO1 enzymatic activity in the sensitization phase, but not after triggering of arthritis, subdued the IFN-alpha-induced inhibition of mBSA-induced proliferation. In conclusion, presence of IFN-alpha at Ag sensitization activates an IDO1/TGF-beta-dependent anti-inflammatory program that upon antigenic rechallenge prevents inflammation via pDC.

    Place, publisher, year, edition, pages
    AMER ASSOC IMMUNOLOGISTS, 2016
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-133121 (URN)10.4049/jimmunol.1502125 (DOI)000387965100018 ()27647832 (PubMedID)
    Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2019-02-11
    3. Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
    Open this publication in new window or tab >>Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
    2014 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 95, no 4, p. 661-666Article in journal (Refereed) Published
    Abstract [en]

    Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.

    Place, publisher, year, edition, pages
    Society for Leukocyte Biology, 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102370 (URN)10.1189/jlb.0613320 (DOI)000335346300011 ()24304616 (PubMedID)
    Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2017-12-06
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  • 42.
    Dahlqvist, Johanna
    et al.
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Ekman, Diana
    Stockholm Univ, Sweden.
    Sennblad, Bengt
    Uppsala Univ, Sweden.
    Kozyrev, Sergey V
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Karlsson, Åsa
    Uppsala Univ, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Hellbacher, Erik
    Uppsala Univ, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå Univ, Sweden.
    Berglin, Ewa
    Umeå Univ, Sweden.
    Stegmayr, Bernd
    Umeå Univ, Sweden.
    Baslund, Bo
    Copenhagen Univ Hosp, Denmark.
    Palm, Oyvind
    Oslo Univ Hosp, Norway.
    Haukeland, Hilde
    Martina Hansens Hosp, Norway.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Nephrology. Karolinska Univ Hosp, Sweden; CLINTEC Karolinska Inst, Sweden.
    Segelmark, Mårten
    Lund Univ, Sweden; Skåne Univ Hosp, Sweden.
    Ohlsson, Sophie
    Lund Univ, Sweden; Skåne Univ Hosp, Sweden.
    Mohammad, Aladdin J.
    Lund Univ, Sweden; Univ Cambridge, England.
    Svärd, Anna
    Uppsala Univ, Sweden.
    Pullerits, Rille
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Herlitz, Hans
    Univ Gothenburg, Sweden.
    Söderbergh, Annika
    örebro Univ Hosp, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Rosenberg, Lina Hultin
    Uppsala Univ, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Murén, Eva
    Uppsala Univ, Sweden.
    Omdal, Roald
    Stavanger Univ Hosp, Norway; Univ Bergen, Norway.
    Jonsson, Roland
    Univ Bergen, Norway.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Rönnblom, Lars
    Uppsala Univ, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Knight, Ann
    Uppsala Univ, Sweden.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 8, p. 3461-3470Article in journal (Refereed)
    Abstract [en]

    Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV).

    Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay.

    Results PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.

    Conclusion We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

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  • 43.
    Dahlström, Örjan
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    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.
    The diagnostic accuracies of the 2012 SLICC criteria and the proposed EULAR/ACR criteria for systemic lupus erythematosus classification are comparable2019In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 28, no 6, p. 778-782Article in journal (Refereed)
    Abstract [en]

    In a joint effort, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) recently proposed new criteria for the classification of systemic lupus erythematosus (SLE) with the overarching goal to identify potential participants for clinical studies. Herein, we present the first independent evaluation of these criteria in comparison with older classification grounds using an adult Scandinavian study population of confirmed SLE cases and individuals with SLE-mimicking conditions. We included 56 confirmed SLE cases meeting the 1982 ACR criteria (ACR-82) and/or the Fries diagnostic principle (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. The proposed EULAR/ACR criteria showed a diagnostic sensitivity of 93% (95% confidence interval (CI), 0.83-0.98) compared with 83% (95% CI, 0.72-0.91) for the updated ACR criteria from 1997. The diagnostic accuracy of all tested classification grounds was fairly similar, achieving approximately 85%. However, the disease specificity of the EULAR/ACR criteria reached only 73% (95% CI, 0.59-0.83), which was comparable with the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria, 75% (95% CI, 0.61-0.85), but clearly lower than for ACR-82, 94% (95% CI, 0.83-0.99). In this first independent evaluation of a limited number of cases, we found comparable results with respect to diagnostic sensitivity, specificity and accuracy regarding the SLICC-12 and the proposed EULAR/ACR classification criteria. However, their specificity for SLE appeared to be lower compared with ACR-82.

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  • 44. Order onlineBuy this publication >>
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies: Implications for pathogenesis, classification and diagnosis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.

    Aims: We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle  fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.

    The studies: We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.

    Conclusion: We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.

    List of papers
    1. Classification and Diagnostic Investigation in Inflammatory Myopathies: A Study of 99 Patients
    Open this publication in new window or tab >>Classification and Diagnostic Investigation in Inflammatory Myopathies: A Study of 99 Patients
    2013 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 40, no 7, p. 1173-1182Article in journal (Refereed) Published
    Abstract [en]

    Objective. Insights into the pathogenesis of inflammatory myopathies have led to new diagnostic methods. The aims of our study were (1) to evaluate the consequences of using the classification of Amato/European Neuromuscular Centre Workshop (ENMC), compared to that of Bohan and Peter; and (2) to evaluate any diagnostic benefit in using an extended pathological investigation. less thanbrgreater than less thanbrgreater thanMethods. From a consecutive retrospective database, we evaluated 99 patients for classification. Patients with inclusion body myositis (IBM) were classified according to Griggs, et al. In addition to routine stainings and immunohistochemistry, a multilevel serial sectioning procedure was performed on paraffin-embedded material, to identify scarce pathological findings. less thanbrgreater than less thanbrgreater thanResults. Classification according to Bohan and Peter could be performed for 83 of the 99 patients, whereas only 60 patients met the Amato/ENMC criteria, the latter resulting in the following diagnostic groups: IBM (n = 18), nonspecific myositis (n = 14), polymyositis (n = 12), dermatomyositis (n = 10), dermatomyositis sine dermatitis (n = 5), and immune-mediated necrotizing myopathy (n = 1). Most of the Amato/ENMC diagnostic groups harbored patients from several of the Bohan and Peter groups, which included a substantial group lacking proximal muscle weakness. The serial sectioning procedure was essential for classification of 9 patients (15%), and led to a more specific diagnosis for 13 patients (22%) according to Amato/ENMC. less thanbrgreater than less thanbrgreater thanConclusion. The classification of Amato/ENMC was more restrictive, forming groups based on clinical criteria and specified myopathological findings, which clearly differed from the groups of the Bohan and Peter classification. An extended pathological investigation increased the diagnostic yield of a muscle biopsy and highlights the quantity and specificity of certain pathological findings.

    Place, publisher, year, edition, pages
    Journal of Rheumatology, 2013
    Keywords
    INFLAMMATORY MYOPATHIES, IDIOPATHIC INFLAMMATORY MYOPATHIES, POLYMYOSITIS, DERMATOMYOSITIS, INCLUSION BODY MYOSITIS
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96992 (URN)10.3899/jrheum.120804 (DOI)000321993800023 ()
    Note

    Funding Agencies|University Hospital Linkoping||County Council of Ostergotland||

    Available from: 2013-09-02 Created: 2013-09-02 Last updated: 2020-01-16
    2. Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle
    Open this publication in new window or tab >>Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle
    2009 (English)In: NEUROMUSCULAR DISORDERS, ISSN 0960-8966, Vol. 19, no 6, p. 412-417Article in journal (Refereed) Published
    Abstract [en]

    The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

    Keywords
    Inflammatory myopathy, Apoptosis, Bcl-2, TRAIL, Fas and Fas-L
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19795 (URN)10.1016/j.nmd.2009.03.008 (DOI)
    Available from: 2009-08-10 Created: 2009-08-10 Last updated: 2020-01-16
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    The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies: Implications for pathogenesis, classification and diagnosis
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  • 45.
    Danielsson, Olof
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Häggqvist, Bo
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Skeletal muscle immunohistochemistry of acquired and hereditary myopathies2021In: Current Opinion in Rheumatology, ISSN 1040-8711, E-ISSN 1531-6963, Vol. 33, no 6, p. 529-536Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review The continued development in the field of immunohistochemistry (IHC) has improved the ability to diagnose muscle diseases. Many hereditary diseases are diagnosed by the absence or abnormal localization of proteins. Detection of secondary pathological protein expression is also used in diagnostics, and to study disease processes. We relate and discuss recent reports, where IHC has been an important tool in the investigation of muscle diseases. Recent findings In idiopathic inflammatory myopathies, IHC has extended its role to diagnose subgroups. This is most evident concerning immune-mediated necrotizing myopathy and antisynthetase syndrome. The availability of new antibodies has increased the sensitivity of a muscle biopsy to diagnose several hereditary myopathies. The introduction of protein restoration therapies in muscular dystrophies also comes with the need to detect and measure protein levels. For the study of disease processes at the protein level, in both acquired and hereditary myopathies IHC, often combined with gene studies, PCR-based methods, western blotting and electron microscopy, continues to bring forth interesting results. IHC is an integrated tool in muscle pathology, where recent studies contribute to improved diagnostic skills and increased insights into disease processes.

  • 46.
    Davidson, Lee Ti
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine in Linköping.
    Gauffin, Emilia
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Henanger, Preben
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Wajda, Maciej
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Wilhelms, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine in Linköping.
    Ekman, Bertil
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Arnqvist, Hans
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Schilling, Martin
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine in Linköping.
    Chisalita, Ioana Simona
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Admission of patients with chest pain and/or breathlessness from the emergency department in relation to risk assessment and copeptin levels - an observational study2022In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 127, no 1, article id e8941Article in journal (Refereed)
    Abstract [en]

    Background: One of the most critical decisions that emergency department (ED) physicians make is the discharge versus admission of patients. We aimed to study the association of the decision in the ED to admit patients with chest pain and/or breathlessness to a ward with risk assessment using the Rapid Emergency Triage and Treatment System (RETTS), the National Early Warning Score (NEWS), and plasma levels of the biomarkers copeptin, midregional proadrenomedulin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP). Methods: Patients presenting at the ED with chest pain and/or breathlessness with less than one week onset were enrolled. Patients were triaged according to RETTS. NEWS was calculated from the vital signs retrospectively. Results: Three hundred and thirty-four patients (167 males), mean age 63.8 +/- 16.8 years, were included. Of which, 210 (62.8%) patients complained of chest pain, 65 (19.5%) of breathlessness, and 59 (17.7%) of both. Of these, 176 (52.7%) patients were admitted to a ward, and 158 (47.3%) patients were discharged from the ED. In binary logistic models, age, gender, vital signs (O-2 saturation and heart rate), NEWS class, and copeptin were associated with admission to a ward from the ED. In receiver-operating-characteristics (ROC) analysis, copeptin had an incremental predictive value compared to NEWS alone (P = 0.002). Conclusions: Emergency physicians decisions to admit patients with chest pain and/or breathlessness from the ED to a ward are related to age, O-2 saturation, heart rate, NEWS category, and copeptin. As an independent predictive marker for admission, early analysis of copeptin might be beneficial when improving patient pathways at the ED.

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  • 47.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Lindström, Ulf
    Univ Gothenburg, Sweden.
    Bower, Hannah
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden.
    Comparison of treatment retention of originator vs biosimilar products in clinical rheumatology practice in Sweden2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 9, p. 3596-3605Article in journal (Refereed)
    Abstract [en]

    Objectives To compare treatment retention between biosimilars and their originator products among first starters (etanercept, infliximab, adalimumab and rituximab), as well as after non-medical switch. Methods Patients with rheumatic diseases starting, for the first time, an originator or biosimilar etanercept, infliximab, adalimumab or rituximab were identified in the national Swedish Rheumatology Quality Register. Moreover, patients switching from an originator to its biosimilar were identified and individually matched to patients continuing on the originator. One-year treatment retention was calculated and hazard ratios (HR) for discontinuation with 95% CIs were estimated, adjusting for comorbidities and socio-economic factors. Results In total, 21 443 first treatment courses were identified. The proportion of patients still on the drug at 1 year and the HR for discontinuation revealed no differences across adalimumab (Humira, Imraldi, Amgevita and Hyrimoz) nor across rituximab products (Mabthera, Ritemvia/Truxima and Rixathon). The proportions on the drug at 1 year were similar for Benepali (77%) and Enbrel (75%) and the adjusted HR for Benepali compared with Enbrel was 0.91 (95% CI 0.83, 0.99). For infliximab, the proportion still on the drug at 1 year was 67% for Remicade and 66% for Remsima/Inflectra and the HR compared with Remicade was 1.16 (95% CI 1.02, 1.33). Among 2925 patients switching from an originator drug to one of its biosimilars, we noted no statistically significant or clinically relevant differences in drug survival compared with those who remained on originator therapy. Conclusion This large observational study supports the equivalence of biologic DMARD biosimilar products and originators when used in routine rheumatology care.

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  • 48.
    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, 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.

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  • 49.
    Dong, Huan-Ji
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Rivano Fischer, Marcelo
    Department of Health Sciences, Research Group Rehabilitation Medicine, Lund University, Lund, Sweden; Department of Neurosurgery and Pain Rehabilitation, Skåne University Hospital, Lund, Sweden.
    Gerdle, Björn
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Lose Pain, Lose Weight, and Lose Both: A Cohort Study of Patients with Chronic Pain and Obesity Using a National Quality Registry2021In: Journal of Pain Research, E-ISSN 1178-7090, Vol. 14, p. 1863-1873Article in journal (Refereed)
    Abstract [en]

    Background: It is known that chronic pain makes it difficult to lose weight, but it is unknown whether obese patients (body mass index ≥30 kg/m2) who experience significant pain relief after interdisciplinary multimodal pain rehabilitation (IMMPR) lose weight.

    Objective: This study investigated whether obese patients with chronic pain lost weight after completing IMMPR in specialist pain units. The association of pain relief and weight change over time was also examined.

    Methods: Data from obese patients included in the Swedish Quality Registry for Pain Rehabilitation for specialized pain units were used (N=224), including baseline and 12-month follow-up after IMMPR from 2016 to 2018. Patients reported body weight and height, pain aspects (eg, pain intensity), physical activity behaviours, psychological distress, and health-related quality of life (HRQoL). A reduction of at least 5% of initial weight indicates clinically significant weight loss. Patients were classified into three groups based on the pain relief levels after IMMPR: pain relief of clinical significance (30% or more reduction of pain intensity); pain relief without clinical significance (less than 30% reduction of pain intensity); and no pain relief. Linear mixed regression models were used to examine the weight changes among the groups with different pain relief levels.

    Results: A significant reduction of pain intensity was found after IMMPR (p < 0.01, effect size Cohen's d = 0.34). A similar proportion of patients in the three groups with different pain relief levels had clinically significant weight loss (20.2%~24.3%, p = 0.47). Significant improvements were reported regarding physical activity behaviour, psychological distress, and HRQoL, but weight change was not associated with changes of pain intensity.

    Conclusion: About one-fifth of obese patients achieved significant weight reduction after IMMPR. Obese patients need a tailored pain rehabilitation program incorporating a targeted approach for weight management.

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  • 50.
    Ekman, Diana
    et al.
    Stockholm Univ, Sweden.
    Sennblad, Bengt
    Stockholm Univ, Sweden.
    Knight, Ann
    Uppsala Univ, Sweden.
    Karlsson, Asa
    Uppsala Univ, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Berglin, Ewa
    Umea Univ, Sweden.
    Stegmayr, Bernd
    Umea Univ, Sweden.
    Baslund, Bo
    Rigshosp, Denmark.
    Palm, Oyvind
    Oslo Univ Hosp, Norway.
    Haukeland, Hilde
    Martina Hansens Hosp, Norway.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Segelmark, Marten
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Ohlsson, Sophie
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Mohammad, Aladdin J.
    Lund Univ, Sweden; Univ Cambridge, England.
    Svard, Anna
    Uppsala Univ, Sweden.
    Pullerits, Rille
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Herlitz, Hans
    Univ Gothenburg, Sweden.
    Soderbergh, Annika
    Orebro Univ Hosp, Sweden.
    Omdal, Roald
    Stavanger Univ Hosp, Norway; Univ Bergen, Norway.
    Jonsson, Roland
    Univ Bergen, Norway.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Dahlqvist, Johanna
    Uppsala Univ, Sweden; Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis2023In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 62, no 9, p. 3213-3218Article in journal (Refereed)
    Abstract [en]

    Objective To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 x 10(-4), OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

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