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  • 901. Tornqvist, Lars
    et al.
    Husmark, Tomas
    Lindqvist, Ulla R. C.
    Alenius, Gerd-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Larsson, Per
    Teleman, Annika
    Geijer, Mats
    Kristensen, Lars Erik
    Thyberg, Ingrid
    Theander, Elke
    Health-Related Quality Of Life In Early Psoriatic Arthritis In Comparison With Early Rheumatoid Arthritis. A 5-Year Follow-Up Report From The Swedish Early Psoriatic Arthritis Registry and The Swedish Early Intervention In RA Registry2013Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, nr Special issue, Supplement 10, s. S142-S142, Meeting Abstract: 329Artikel i tidskrift (Övrigt vetenskapligt)
  • 902. Trokovic, Nina
    et al.
    Pöllänen, Raimo
    Porola, Pauliina
    Stegaev, Vasily
    Hetzel, Udo
    Tivesten, Åsa
    Engdahl, Cecilia
    Carlsten, Hans
    Forsblad-d'Elia, Helena
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Fagman, Johan Bourghardt
    Lagerquist, Marie
    Konttinen, Yrjö T
    Exosomal secretion of death bullets: a new way of apoptotic escape?2012Ingår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 303, nr 8, s. E1015-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ovariectomy/estrogen deficiency causes selective apoptosis of the serous epithelial cells of the submandibular glands (SMG) in female mice. Because such apoptosis does not occur in healthy, estrogen-deficient male mice, it was hypothesized that dihydrotestosterone (DHT) protects epithelial SMG cells against apoptosis. The antiapoptotic effect of DHT on human epithelial HSG cells exposed to tumor necrosis factor-α and cycloheximide was studied. Correspondingly, the proapoptotic effect of androgen deficiency was studied in orchiectomized (ORX) androgen-knockout (ARKO) and wild-type (WT) mice. The health state of the SMG cells was studied with Alcian blue-periodic acid Schiff (AB-PAS) and amylase staining and transmission electron microscopy (TEM). The eventual protective antiapoptotic effect of dehydroepiandrosterone (DHEA) treatment was tested in this model. Apoptosis was assessed using immunohistochemisty of cleaved effector caspase-3 and its activator caspase-8 and the TUNEL assay. To test for the bioavailability, intracrine metabolism and sex steroid effects of DHEA, cystein-rich secretory protein-3 (CRISP-3), and leucine-isoleucine-valine transport system 1 (LIV-1) were used as androgen- and estrogen-regulated biomarkers, respectively. DHT protected HSG cells against induced apoptosis. In mice, androgen deficiency resulted in extensive activation of apoptotic caspase-8/3 cascade in serous epithelial cells. However, in salivary glands, active caspases were not translocated to nuclei but secreted to salivary ducts in exosome-like particles, which are associated with weak AB-PAS and amylase staining of the androgen-deprived cells and reduced number of intracellular secretory granules. DHEA treatment suppressed induction of proapoptotic caspases and almost normalized mucins and amylase and ultramophology of the serous epithelial cells in WT ORX but not ARKO ORX mice. According to the CRISP-3 and LIV-1 markers, DHEA probably exerted its effects via intracrine conversion to DHT.

  • 903. Turesson, C.
    et al.
    Bergstrom, U.
    Truedsson, L.
    Sohrabian, Azita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Jacobsson, L.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Patterns of isotype distribution in circulating antibodies in the pre-clinical phase of rheumatoid arthritis and their relationship to smoking2014Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, nr S127, s. 22-22Artikel i tidskrift (Övrigt vetenskapligt)
  • 904. Turesson, C.
    et al.
    Bergstrom, U.
    Truedsson, L.
    Sohrabian, Azita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Jacobsson, L. T.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Patterns of Isotype Distribution in Circulating Antibodies in the Pre-Clinical Phase of Rheumatoid Arthritis and their Relation to Smoking2014Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, s. 510-510Artikel i tidskrift (Övrigt vetenskapligt)
  • 905.
    Törring, Ove
    et al.
    Karolinska Institutet, Institution for Clinical Science and Education, Stockholm, Sweden .
    Watt, Torquil
    Copenhagen University Hospital Rigshospitalet, Department of Medical Endocrinology, Copenhagen, Danmark, Denmark .
    Sjölin, Gabriel
    Department of Surgery, Örebro University Hospital, Örebro, Sweden .
    Byström, Kristina
    Dept. of Medicine, Örebro University Hospital, Örebro, Sweden .
    Abraham-Nordling, Mirna
    Karolinska Institute, Institute of molecular medicine and surgery, Colorectal surgery, Karolinska University Hospital, Stockholm, Sweden .
    Calissendorff, Jan
    Dept. of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
    Cramon, Per
    Copenhagen University Hospital Rigshospitalet, Department of Endocrinology, Copenhagen, Denmark .
    Filipsson Nyström, Helena
    Dept. of Endocrinology, Sahlgrenska University Hospital, Göteborg, Sweden .
    Hallengren, Bengt
    Dept. of Endocrinology, Skånes University Hospital, Malmö, Sweden.
    Holmberg, Mats
    ANOVA, Karolinska University Hospital, Stockholm, Sweden.
    Khamisi, Selwan
    Dept. of Endocrinology, Uppsala University Hospital, Uppsala, Sweden .
    Lantz, Mikael
    Lund University, Department of Clinical Sciences, Diabetes & Endocrinology, Department of Endocrinology, Skåne University Hospital, Malmö, Sweden .
    Wallin, Göran
    Örebro universitet, Institutionen för medicinska vetenskaper. Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; Örebro University, Dept of Surgery, Faculty of Medicine and Health, Sweden, Sweden .
    Impaired quality of life after radioiodine therapy compared with antithyroid drugs or surgical treatment for Graves' hyperthyroidism. A long-term follow-up with ThyPRO and SF-362019Ingår i: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Hyperthyroidism is known to have a significant impact on the quality of life (QoL) at least in the short term. The purpose of the present study was to assess QoL in patients at 6-10 years after treatment for Graves´ disease (GD) with radioiodine (RAI) to those treated with thyroidectomy or antithyroid drugs (ATD) as assessed with both a thyroid-specific (ThyPRO) and general (SF-36) QoL surveys.

    METHODS: We evaluated 1186 GD patients in a sub-cohort from an incidence study 2003-2005 which had been treated according to routine clinical practice at seven participating centers. Patients were included if they had returned the ThyPRO (n=975) and/or the SF-36 questionnaire (n=964) and informed consent at follow-up. Scores from ThyPRO were compared with scores from a general population sample (n=712), using multiple linear regression adjusting for age and gender as well as multiple testing. Treatment related QoL outcome for ATD, RAI and surgery were compared including adjustment for the number of treatments received, sex, age and co-morbidity.

    RESULTS: Regardless of treatment modality, patients with GD had worse thyroid-related QoL 6-10 years after diagnosis compared with the general population. Patients treated with RAI had worse thyroid-related and general QoL than patients treated with ATD or thyroidectomy on the majority of QoL-scales. Sensitivity analyses supported the relative negative comparative effects of RAI treatment on QoL in patients with hyperthyroidism.

    CONCLUSIONS: Graves´ disease is associated with a lower QoL many years after treatment compared to the general population. In a previous, small RCT we did not show any difference in patient satisfaction years after ATD, RAI or surgery. We now report that in a large non-randomized cohort, patients who received RAI had adverse scores on ThyPRO and SF-36. These findings in a Swedish population are limited by comparison to normative data from Denmark, by older age and possibly a more prolonged course in those patients who received radioiodine, and a lack of information regarding thyroid status at the time of evaluation. The way RAI may adversely affect QoL is unknown but since the results may be important for future considerations regarding treatment options for GD they need to be substantiated in further studies.

  • 906. Uddhammar, A
    et al.
    Sundqvist, K G
    Ellis, B
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Cytokines and adhesion molecules in patients with polymyalgia rheumatica1998Ingår i: British Journal of Rheumatology, ISSN 0263-7103, E-ISSN 1460-2172, Vol. 37, nr 7, s. 766-769Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Serum levels of interleukin-1 beta (IL-1 beta), IL-1 receptor antagonist (IL-1ra), tumour necrosis factor alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin were measured in 15 patients with newly diagnosed polymyalgia rheumatica (PMR) before and after 3 months of corticosteroid therapy. Both IL-6 and IL-1ra were significantly increased in untreated PMR and remained elevated compared with controls during therapy, although significantly only for sIL-1ra. sICAM-1 was raised in 12/15 (87%) patients at diagnosis and remained high in 10/14 (71%) patients; soluble E-selectin levels were initially raised in 6/15 (40%) patients and decreased with therapy in those with the highest levels. IL-6, IL-1ra and sICAM-1 are sensitive indicators of continuing immunological activation in PMR; the advantages of these markers in assessing the response to therapy should be investigated in a longitudinal study.

  • 907. Uddhammar, Agneta
    et al.
    Eriksson, Anna-Lena
    Nyström, Lennarth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Stenling, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Increased mortality due to cardiovascular disease in patients with giant cell arteritis in Northern Sweden2002Ingår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 29, nr 4, s. 737-742Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. To study the cause of death pattern in patients with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR). and to analyze the effect of the disease, or its therapy, on the risk of a cardiovascular event (CVE).

    Methods. Patients with biopsy proven GCA or with PMR, whose condition was diagnosed between 1973 and 1979, were followed until December 31, 1995. The standardized mortality ratio (SMR) was estimated using data for the population of V sterbotten, Northern Sweden, as reference value. Information for sex, age at diagnosis, erythrocyte sedimentation rate (ESR) at diagnosis, corticosteroid therapy, comorbidity from diagnosis, and date and cause of death was collected.

    Results. A total of 136 patients with GCA and 35 with PMR were identified. At the time of followup 114 patients with GCA and 25 with PMR were deceased. The overall mortality was significantly increased in the female patients, SMR = 133 (95% Cl 110-162). Death due to cardiovascular disease (CVD) was significantly increased in both women and men, SMR = 149 (95% CI 118-189) and 158 (95% Cl 112-224), respectively, and mainly due to ischemic heart disease. An excess mortality was found in women with the hi-hest ESR, the highest prescribed dose of prednisolone at diagnosis, or a daily prednisolone dose of 10 mg or more one year after diagnosis. In multiple Cox regression analysis, male sex and hypertension significantly increased the risk of a CVE.

    Conclusion. Death due to CVD was increased in patients with GCA. Increased mortality was related to either the corticosteroid therapy itself or insufficient control of inflammation.

  • 908. van Delft, Myrthe A. M.
    et al.
    Verheul, Marije K.
    Burgers, Leonie E.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    van der Helm-van Mil, Annette H. M.
    Huizinga, Tom W. J.
    Toes, René E. M.
    Trouw, Leendert A.
    The anti-carbamylated protein antibody response is of overall low avidity despite extensive isotype switching2018Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 57, nr 9, s. 1583-1591Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To better understand the contribution of autoantibodies in RA and the biology of their responses, we evaluated the avidity of the anti-carbamylated protein (anti-CarP) antibody response.

    Methods: The avidity of anti-CarP antibody, ACPA and anti-tetanus toxoid IgG were determined using elution assays. Anti-CarP IgG avidity was measured in sera of 107 RA patients, 15 paired SF and serum samples and 8 serially sampled sera before and after disease onset.

    Results: The avidity of anti-CarP IgG is low compared with the avidity of anti-tetanus toxoid IgG present in the same sera. Likewise, although less pronounced, anti-CarP also displayed a lower avidity as compared with the avidity of ACPA IgG. No difference in anti-CarP IgG avidity is observed between ACPA positive or ACPA negative patients. Anti-CarP IgG avidity is higher in anti-CarP IgM-negative compared with IgM-positive individuals. Furthermore, the anti-CarP avidity in serum is higher than in SF. Using samples of individuals that over time developed RA we observed no anti-CarP avidity maturation in the years before disease onset. In contrast to ACPA avidity, the anti-CarP avidity is not associated with severity of joint destruction.

    Conclusion: The anti-CarP response is of overall low avidity, even lower than the ACPA IgG avidity, and does not show apparent avidity maturation before or around disease onset. Overall, isotype switch and avidity maturation seem to be uncoupled as isotype switch occurs without avidity maturation, pointing towards a commonality in the regulation of both autoantibody responses as opposed to the pathways governing recall responses.

  • 909. van Steenbergen, H. W.
    et al.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    van Nies, J. A. B.
    Berglin, Ewa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Huizinga, T. W. J.
    Gregersen, P. K.
    van der Helm-van Mil, A. H. M.
    Does a genetic variant in FOXO3A predict a milder course of rheumatoid arthritis?2014Ingår i: Arthritis and Rheumatology, ISSN 2326-5191, Vol. 66, nr 6, s. 1678-1681Artikel i tidskrift (Övrigt vetenskapligt)
  • 910. van Steenbergen, H. W.
    et al.
    Raychaudhuri, S.
    Rodríguez-Rodríguez, L.
    Rantapää-Dahlqvist, Solbritt
    Berglin, Ewa
    Toes, R. E. M.
    Huizinga, T. W. J.
    Fernández-Gutiérrez, B.
    Gregersen, P. K.
    van der Helm-van Mil, A. H. M.
    Association of valine and leucine at HLA-DRB1 position 11 with radiographic progression in rheumatoid arthritis, independent of the shared epitope alleles but not independent of anti-citrullinated protein antibodies2015Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr 4, s. 877-886Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: For decades it has been known that the HLA-DRB1 shared epitope (SE) alleles are associated with an increased risk of development and progression of rheumatoid arthritis (RA). Recently, the following variations in the peptide-binding grooves of HLA molecules that predispose to RA development have been identified: Val and Leu at HLA-DRB1 position 11, Asp at HLA-B position 9, and Phe at HLA-DPB1 position 9. This study was undertaken to investigate whether these variants are also associated with radiographic progression in RA, independent of SE and anti-citrullinated protein antibody (ACPA) status.

    METHODS: A total of 4,911 radiograph sets from 1,878 RA patients included in the Leiden Early Arthritis Clinic (The Netherlands), Umeå (Sweden), Hospital Clinico San Carlos-Rheumatoid Arthritis (Spain), and National Data Bank for Rheumatic Diseases (US) cohorts were studied. HLA was imputed using single-nucleotide polymorphism data from an Immunochip, and the amino acids listed above were tested in relation to radiographic progression per cohort using an additive model. Results from the 4 cohorts were combined in inverse-variance weighted meta-analyses using a fixed-effects model. Analyses were conditioned on SE and ACPA status.

    RESULTS: Val and Leu at HLA-DRB1 position 11 were associated with more radiographic progression (meta-analysis P = 5.11 × 10(-7)); this effect was independent of SE status (meta-analysis P = 0.022) but not independent of ACPA status. Phe at HLA-DPB1 position 9 was associated with more severe radiographic progression (meta-analysis P = 0.024), though not independent of SE status. Asp at HLA-B position 9 was not associated with radiographic progression.

    CONCLUSION: Val and Leu at HLA-DRB1 position 11 conferred a risk of a higher rate of radiographic progression independent of SE status but not independent of ACPA status. These findings support the relevance of these amino acids at position 11.

  • 911. van Steenbergen, Hanna W
    et al.
    Aletaha, Daniel
    Beaart-van de Voorde, Liesbeth J J
    Brouwer, Elisabeth
    Codreanu, Catalin
    Combe, Bernard
    Fonseca, João E
    Hetland, Merete L
    Humby, Frances
    Kvien, Tore K
    Niedermann, Karin
    Nuño, Laura
    Oliver, Sue
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Raza, Karim
    van Schaardenburg, Dirkjan
    Schett, Georg
    De Smet, Liesbeth
    Szücs, Gabriella
    Vencovský, Jirí
    Wiland, Piotr
    de Wit, Maarten
    Landewé, Robert L
    van der Helm-van Mil, Annette H M
    EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis2017Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, nr 3, s. 491-496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.

    METHODS: The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.

    RESULTS: The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.

    CONCLUSIONS: A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.

  • 912. van Steenbergen, Hanna W.
    et al.
    Rodriguez-Rodriguez, Luis
    Berglin, Ewa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Zhernakova, Alexandra
    Knevel, Rachel
    Ivorra-Cortes, Jose
    Huizinga, Tom W. J.
    Fernandez-Gutierrez, Benjamin
    Gregersen, Peter K.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    van der Helm-van Mil, Annette H. M.
    A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, artikel-id 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts. Methods: In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients. Results: No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 x 10(-7)); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 x 10(-8). Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5. Conclusion: Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.

  • 913. van Vollenhoven, R F
    et al.
    Ernestam, S
    Geborek, P
    Petersson, I F
    Cöster, L
    Waltbrand, E
    Zickert, A
    Theander, J
    Thörner, A
    Hellström, H
    Teleman, A
    Dackhammar, C
    Akre, F
    Forslind, K
    Ljung, Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Oding, R
    Chatzidionysiou, A
    Wörnert, M
    Bratt, J
    Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial.2009Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 374, nr 9688, s. 459-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: New treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis.

    METHODS: We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3-4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004.

    FINDINGS: 487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10-2.30], p=0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group.

    INTERPRETATION: In patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs.

    FUNDING: Swedish Rheumatism Association, Schering-Plough.

  • 914.
    van Vollenhoven, Ronald F.
    et al.
    Karolinska Inst, Inflammatory Dis ClinTRID, Unit Clin Therapy Res, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Rheumatol Clin, Stockholm, Sweden..
    Ostergaard, Mikkel
    Univ Copenhagen, Glostrup Hosp, Ctr Rheumatol & Spine Dis, Fac Hlth Sci,Copenhagen Ctr Arthrit Res, Copenhagen, Denmark..
    Leirisalo-Repo, Marjatta
    Univ Helsinki, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Uhlig, Till
    Diakonhjemmet Hosp, Dept Rheumatol, Natl Advisory Unit Rehabil Rheumatol, Oslo, Norway..
    Jansson, Marita
    Pfizer Sweden, Sollentuna, Sweden..
    Larsson, Esbjorn
    Pfizer Sweden, Sollentuna, Sweden..
    Brock, Fiona
    Quanticate, Stat Consultancy, Hitchin, England..
    Franck-Larsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Gastroenterologi/hepatologi.
    Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis2016Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, nr 1, s. 52-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept (ETN) dose maintenance, reduction or withdrawal on patients with rheumatoid arthritis (RA) who had already achieved stable low disease activity (LDA) on ETN 50 mg + methotrexate (MTX). Methods Patients with RA (n=91) and stable LDA with ETN 50 mg once weekly (QW)+ MTX were included. After 8 weeks with unchanged treatment, 73 patients were randomised in a double-blind design to ETN 50 mg QW+MTX (ETN50), ETN 25 mg QW+MTX (ETN25) or placebo QW+MTX (PBO) for 48 weeks. Patients who flared were declared failures and treated with open-label ETN50 until week 48. The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks. Results The proportion of non-failure patients was significantly lower with ETN50 (52%; p=0.007) and ETN25 (44%; p=0.044) versus PBO (13%). Median time to failure was significantly shorter with PBO (6 weeks) compared with ETN50 (48 weeks; p=0.001) and ETN25 (36 weeks; p<0.001). The majority of patients who flared regained LDA with open-label ETN50 quickly. Adverse events were consistent with the known side effect profiles of these medications. Conclusions In patients with established RA who have achieved stable LDA on ETN50+MTX, continuing both is superior to PBO+MTX. Reduced dose ETN was also more effective than PBO in maintaining a favourable response, suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA.

  • 915. Vasaitis, L
    et al.
    Nordmark, G
    Theander, E
    Backlin, C
    Smedby, K E
    Askling, J
    Rönnblom, L
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome.2018Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.

    METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.

    RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.

    CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

  • 916.
    Vasaitis, Lilian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    IgG4-related disease: A relatively new concept for clinicians2016Ingår i: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828, Vol. 27, s. 1-9Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    IgG4-related disease (IgG4-RD) is a recently recognized chronic fibrotic inflammation, which can affect almost every organ, and may come to clinical attention first due to visible organ swelling or organ dysfunction, or is identified incidentally by imaging and specific biopsy. The disorder has an allergic background and is immune-mediated. Up-regulated responses of T helper 2 and T regulatory cells and their cytokines play a major role in disease progression. About 30–50% of patients are atopic or have mild eosinophilia. IgG4-RD predominantly affects middle-aged male patients. The cornerstones of diagnosis of the disease are compatible clinical features and typical histopathology. Swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis (AIP) are the most common manifestations of the disease.  However, other tissues and organs, such as retroperitoneum, lung, kidney, aorta, upper airways, thyroid gland, meninges, heart, mesenterium and skin may be involved. Typical histopathology is lymphoplasmacytic infiltration abundant in IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. Elevated serum IgG4 concentration supports the diagnosis. Characteristic imaging features such as a “capsule-like rim” surrounding the pancreatic lesions is highly specific to type 1 AIP.18F-fluorodeoxyglucose positron emission tomography/computed tomography enables mapping the sites of inflammation, permits evaluation of the extent of the disease, helps in guiding biopsy decision, and may be used in monitoring response to treatment. Glucocorticoids alone or in combination with B-cell depletion with rituximab induces prompt clinical response to IgG4-RD.

    This article reviews the current understanding, different clinical manifestations, and approaches to diagnosis and treatment of IgG4-RD.

  • 917.
    Vasaitis, Lilian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lymphoma studies in patients with Sjögren's syndrome2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Patients with primary Sjögren’s syndrome (pSS) are at increased risk of developing malignant lymphoma. The studies in this thesis aim at broadening our understanding of the association between these two conditions.

    Germinal centre (GC)-like structures were found in minor salivary gland biopsies taken at the time of pSS diagnosis in 25% of 175 studied patients. Lymphoma development was observed in 86% of the GC-positive pSS patients and 14% of the GC-negative patients. GC-like structures in salivary gland biopsies at pSS diagnosis might identify pSS patients at high risk for later lymphoma development.

    We used the National Patient Register and the Cancer Register to identify pSS patients with lymphoid malignancy for the following studies. The lymphoma tissues were reviewed and classified according to the WHO classification.

    In a study of 79 patients with available lymphoma tissues, we identified histopathological and clinical features compatible with IgG4-related disease (IgG4-RD) in one patient (1.3%). Histological features of IgG4-RD in lymphoma tissue in patients with an initial pSS diagnosis seem to be rare but, if present, may indicate underlying IgG4-RD.

    We identified and compared pSS patients with (n=18/17%) and without (n=87) pre-existing lymphoma at pSS diagnosis and found similar pSS characteristics in both groups. Mucosa-associated lymphoid tissue (MALT) lymphoma in salivary glands was more common in patients with pre-existing lymphoma. The findings support the removal of pre-existing lymphoma as a general exclusion criterion for a pSS diagnosis in classification criteria. Further, the findings suggest an investigation for pSS in patients presenting with MALT lymphoma in salivary glands.

    We compared the distribution of lymphoma subtypes with a general population reference. Both diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma (MZL) (31%) were common, but only MZL (MALT lymphomas) occurred at an increased relative frequency compared to the general population.

    Men constituted 15% of 105 pSS patients with lymphoma. Men had a shorter time between the pSS and lymphoma diagnoses and more often had lymphoma in the salivary glands compared with women. Increased awareness of signs of lymphoma in salivary glands already during the first years after pSS diagnosis is justified in men with pSS.

  • 918.
    Vasaitis, Lilian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Population-based study of primary Sjögren’s syndrome and lymphoma: lymphoma subtypes, clinical characteristics, and sex differencesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective. To examine lymphoma subtypes, clinical characteristics and sex differences of primary Sjögren’s syndrome (pSS) patients with lymphoma in a population-based setting.

     Methods. We identified 224 patients with both Sjögren’s syndrome and lymphoma diagnoses by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007. Clinical data was collected from medical records and diagnoses validated. Lymphoma specimens were classified using the WHO classification and Epstein-Barr virus (EBV) was searched for by EBER in situ hybridization. The lymphoma subtype distribution was compared with the Swedish Lymphoma Register as a reference.  After exclusions (where pSS or lymphoma diagnoses could not be confirmed) 105 patients remained in the study.

    Results. Diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma (MZL) (31%) were the two most common lymphoma subtypes. The proportion of DLBCL was not increased compared to the general population reference (32%, p=1), in contrast to MZL (general population 5%, p<0.0001). Similar proportions were found of the germinal center B-cell-like and activated B-cell-like subtypes of DLBCL. EBV was found in 22% of DLBCLs and in 80% of Hodgkin lymphomas but was not detected in the MZL tissues.

    Compared to DLBCL, MALT lymphoma (28/31 of all MZLs) was diagnosed at a younger age (55 vs. 67 years, p=0.0001), and earlier after patient-reported sicca onset (seven vs. 18 years, p=0.0001) and pSS diagnosis (two vs. nine years, p=0.0005).

    Sixteen of the pSS-lymphoma cases were men (15%), twice the proportion in general pSS populations. Compared to women, men had a shorter median time from pSS diagnosis to lymphoma diagnosis (one vs. eight years, p=0.0003) and more often had lymphoma in the salivary glands (56% vs. 29%, p=0.04).

    Conclusion. Both DLBCL and MZL are common in pSS patients, but only MZL/MALT lymphoma occurs at an increased relative frequency in pSS compared to the general population. The identified sex differences support an increased awareness of signs of lymphoma in men already the first years after pSS diagnosis. 

  • 919.
    Vasaitis, Lilian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Support for removal of lymphoma as an exclusion criterion in classification criteria for primary Sjögren’ s syndromeManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective. Classification criteria for primary Sjögren’s syndrome (pSS) have previously included pre-existing lymphoma as an exclusion criterion for a pSS diagnosis, but the rationale for this exclusion criterion has not been formally studied.

    We, therefore, aimed to explore if there were differences between pSS patients with and without pre-existing lymphoma.

    Methods. Patients registered with ICD-7-10 codes for SS (which capture all reasons for sicca symptoms) and a diagnosis of malignant lymphoma before or after the SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n=224). Clinical data was collected from medical records and the underlying cause of the SS diagnosis code was investigated. Lymphoma diagnoses were evaluated by tissue review. Patient characteristics in pSS patients with and without pre-existing lymphoma were compared by Mann-Whitney and Fisher’s tests.

    Results. A total of 207 SS-lymphoma patients remained after lymphoma tissue review. 107 (52%) of these had pSS according to the treating physician. 18 (17%) had a pre-existing lymphoma at pSS diagnosis. The pSS characteristics were similar in patients with and without pre-existing lymphoma, also in analyses restricted to patients fulfilling the 2002 AECG criteria for pSS. Mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs. 22%, p=0.02), and lymphoma in the salivary glands, (61% vs. 26%, p=0.006) were more common in patients with pre-existing lymphoma.

    Conclusions. Our results support the removal of pre-existing lymphoma as a general exclusion criterion for a pSS diagnosis. The results also suggest that patients with MALT lymphoma or lymphoma in the salivary glands should be investigated for the presence of pSS.

  • 920.
    Vasaitis, Lilian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Askling, J.
    Ekstrom-Smedby, K.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Theander, E.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Comparison of lymphomas in primary and secondary Sjogren's syndrome2014Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, nr suppl. 127, s. 83-83Artikel i tidskrift (Övrigt vetenskapligt)
  • 921.
    Vasaitis, Lilian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Theander, E.
    Lund Univ, Skane Univ Hosp, Dept Rheumatol, Malmo, Sweden..
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Smedby, K. E.
    Karolinska Inst, Dept Med Sci, Clin Epidemiol Unit, Stockholm, Sweden..
    Askling, J.
    Karolinska Inst, Dept Med Sci, Clin Epidemiol Unit, Stockholm, Sweden..
    Sundstrom, C.
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Primary Sjögren's Syndrome and Lymphoma – A Population-Based Study Focused on Lymphoma as Exclusion Criterion for Primary Sjögren's Syndrome Diagnosis2016Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, s. 779-780Artikel i tidskrift (Övrigt vetenskapligt)
  • 922.
    Vasaitis, Lilian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sporadic Occurrence of Non-Diagnosed IgG4-Related Disease in Lymphoma Patients with a Previous Sjogren's Syndrome Diagnosis2015Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, nr 5, s. 407-407Artikel i tidskrift (Övrigt vetenskapligt)
  • 923.
    Vasaitis, Lilian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sporadic occurrence of non-diagnosed IgG4-related disease in lymphoma patients with a previous Sjögren's syndrome diagnosis.2016Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 9-10, s. 1139-1144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder, which may affect many organs, and often comes to clinical attention due to tumor-like organ swelling or is identified incidentally by specific biopsy findings. Typical histopathology of IgG4-RD is lymphoplasmacytic infiltration rich in IgG4 + plasma cells (PCs), storiform fibrosis, and obliterative phlebitis. Patients with sicca symptoms can be misdiagnosed as primary Sjögren's syndrome (pSS) instead of IgG4-RD because of clinical and histopathological similarities. Moreover, an association with lymphoma development is described in both diseases. This study investigated signs of IgG4-RD in a population-based cohort of patients diagnosed with pSS complicated by lymphoma.

    METHODS: Patients with pSS and lymphoma diagnoses and available lymphoma specimens were identified by linkage with the Swedish Patient Register 1964-2007 and the Cancer Register 1990-2007 (n = 79). Clinical data and lymphomas were reviewed and the diagnoses evaluated. All lymphoma tissues and available minor salivary gland biopsies (n = 11) were immunostained for IgG4 + PCs and evaluated for other histopathological signs of IgG4-RD. In a case with specific findings of IgG4-RD, other available tissue specimens of the same patient were investigated for IgG4-RD.

    RESULTS: Only one patient of 79 (1.3%) had >10 IgG4 + PCs/high power field (HPF) in the lymphoma tissue, an unspecified low-grade B-cell lymphoma localized in the submandibular gland. This patient also had other histopathological features of IgG4-RD in the lymphoma and a surgical lung biopsy taken five years before lymphoma diagnosis and, therefore, fulfilled the criteria for IgG4-RD. Occasional IgG4 + PCs (<10/HPF) without signs of IgG4-RD were observed in another six lymphomas. No IgG4 + PCs were identified in the minor salivary gland biopsies.

    CONCLUSION: Histopathological findings of IgG4-RD may co-exist with low malignant B-cell lymphoma in patients with initially suspected pSS and may be associated with an underlying IgG4-RD.

  • 924.
    Vegfors, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Psoriasin (S100A7) contributes to stress-induced angiogenesis in psoriasis by the regulation of angiogenic factors in keratinocytes and promotion of angiogenic properties of dermal endothelial cells2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The S100 protein psoriasin, S100A7, is highly expressed in psoriasis. Vascular modifications occur early in the development of psoriasis and angiogenesis is one of the key features in the pathogenesis of the disease. This study aims to define the angiogenic properties of psoriasin in keratinocytes and to investigate the effects on dermal endothelial cells, thereby promoting angiogenesis in psoriasis. We showed that psoriasin expression, demonstrated by qPCR, is induced by hydrogen peroxide (H2O2) in keratinocytes and by cellular stress, such as hypoxia and cobalt chloride (CoCl2). Down-regulation of psoriasin, by siRNA, decreased the H2O2-induced expression of VEGF, heparin-binding EGF-like growth factor (HB-EGF) and matrix metalloproteinase (MMP)-1, and counteracted the reduction of the anti-angiogenic factor thrombospondin (THBS)-1. Extracellularly psoriasin was found to induce cell proliferation, migration and tube formation to a similar degree as VEGF and to induce the pro-angiogenic factors VEGF and IL-8 in dermal endothelial cells. Furthermore, we demonstrated that psoriasin-induced migration was mediated by the phosphoinositide-3-kinase (PI3K) and nuclear factor-kappa beta (NF-κB) signaling pathways. In conclusion, psoriasin is induced by cellular stress conditions and amplifies H2O2-induced expression of angiogenic factors relevant for psoriasis in keratinocytes. Moreover, psoriasin contributes to key features of the angiogenic process by inducing proliferation, migration and tube formation and increasing pro-angiogenic factors in dermal endothelial cell. Altogether, our data suggest that psoriasin is promoted by oxidative stress and mediate angiogenesis in psoriasis.

  • 925.
    Vegfors, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Psoriasin (S100A7) is regulated by protein kinase C (PKC) and contributes to keratinocyte differentiation by regulating the expression of epidermal differentiation markers2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Psoriasis is a chronic inflammatory skin disease that is characterized by hyperproliferation and a disturbed maturation of the epidermal cells. The differentiation process of keratinocytes in active psoriatic lesions differs from that of normal epidermis, denoted by an altered expression of differentiation markers. Psoriasin, a protein which is highly expressed in psoriasis, is located within the epidermal differentiation complex (EDC), a gene cluster that contains several genes that are important in the terminal differentiation of the human epidermis. The potential role of psoriasin in keratinocyte differentiation remain however unclear. The aim of this present study was to investigate the possible involvement of psoriasin in keratinocyte differentiation. We demonstrated, by immunohistochemical staining, a gradient of psoriasin expression in the psoriatic epidermis, from an undefined or weak expression in the basal layer to an intense expression in the suprabasal differentiated layers. The expression of psoriasin was up-regulated in cultured keratinocytes in response to stimuli known to induce differentiation, such as an elevation of extracellular calcium or  12-Otetradecanoylphorbol-13-acetate (TPA). Down-regulation of psoriasin expression, by siRNA, resulted in decreased expression of the differentiation markers involucrin, desmoglein 1, transglutaminase 1 and CD24. Inhibition of protein kinase C (PKC) counteracted the calciuminduced expression of psoriasin and involucrin. In summary, our data demonstrate that psoriasin is regulated by the PKC signaling pathway and contributes to keratinocyte differentiation by the regulation of differentiation markers.

  • 926. Venalis, P.
    et al.
    Pandya, J.
    Al-Khalili, Lubna
    KTH, Skolan för bioteknologi (BIO), Industriell bioteknologi.
    Hossein, M. S.
    Stache, V.
    Lundberg, I. E.
    Malmström, V.
    Fasth, A. E. R.
    CD28NULL T CELLS KILL AUTOLOGOUS MUSCLE CELLS FROM POLYMYOSITIS PATIENTS IN VITRO BY PERFORIN-DEPENDENT MECHANISMS2014Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, s. 576-576Artikel i tidskrift (Övrigt vetenskapligt)
  • 927. Verheul, Marije K.
    et al.
    Böhringer, Stefan
    van Delft, Myrthe A. M.
    Jones, Jonathan D.
    Rigby, William F. C.
    Gan, Ryan W.
    Holers, V. Michael
    Edison, Jess D.
    Deane, Kevin D.
    Janssen, Koen M. J.
    Westra, Johanna
    Brink, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Huizinga, Tom W. J.
    van der Helm-van Mil, Annette H. M.
    van der Woude, Diane
    Toes, Rene E. M.
    Trouw, Leendert A.
    Triple positivity for anti–citrullinated protein autoantibodies, rheumatoid factor, and anti–carbamylated protein antibodies conferring high specificity for rheumatoid arthritis: implications for very early identification of at‐risk individuals2018Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, nr 11, s. 1721-1731Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: In rheumatoid arthritis(RA), the autoantibodies anti-citrullinated protein antibodies(ACPA) and rheumatoid factor(RF) are commonly used to aid RA diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPA and RF alone. Also, anti-carbamylated protein(anti-CarP) antibodies have diagnostic and prognostic value as the presence of anti-CarP antibodies associates with joint damage in RA patients and with future RA development in arthralgia patients. Therefore, we aimed to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA.

    METHODS: A literature search resulted in twelve studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients or healthy controls, in which data on RF, ACPA and anti-CarP antibody-status was available. Random effects meta-analyses were carried out for several antibody combinations.

    RESULTS: The individual antibodies are highly prevalent in RA(34%-80%) compared to the control groups, but are also present in non-RA controls(0%-23%). To classify most people correctly as RA or non-RA, the combination of ACPA and/or RF often performs well(specificity:65-100, sensitivity:59-88). However, triple positivity for ACPA, RF and anti-CarP antibodies results in a higher specificity(98-100) (accompanied by a lower sensitivity(11-39)).

    CONCLUSIONS: As the rheumatology field is moving towards very early identification of RA and possible screening for individuals at maximum risk in populations with a low pre-test probability, triple positivity provides interesting information on individuals at risk to develop RA.

  • 928. Vikerfors, Anna
    et al.
    Johansson, Anna-Britta
    Gustafsson, Johanna T
    Jönsen, Andreas
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Zickert, Agneta
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sturfelt, Gunnar
    Bengtsson, Anders
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Gunnarsson, Iva
    Elvin, Kerstin
    Svenungsson, Elisabet
    Clinical manifestations and anti-phospholipid antibodies in 712 patients with systemic lupus erythematosus: evaluation of two diagnostic assays2013Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 34, nr 5, s. 345-353Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives

    To evaluate the agreement and performance of two tests for aPLs with regard to association with manifestations of the APS in patients with SLE.

    Methods

    We investigated 712 SLE patients and 280 population controls. Cardiolipin and β2 glycoprotein-I antibodies were measured with routine ELISA and a new automated method. Three positivity cut-offs (99%, 90% of controls and recommended cut-off by manufacturers) were used. Associations with previous thrombotic events, thrombocytopenia and, in a subgroup of patients, obstetric morbidity (n = 296) were evaluated. Results were compared with the LA test, performed in 380 patients.

    Results

    Inter-test agreement was moderate (demonstrated by κ-values 0.16–0.71). Performance of the two tests was similar: at the 99th percentile cut-off, sensitivity for any thrombotic event ranged from 3.7% to 24.8%, while specificity was 84.7–97.7%. Regardless of assay, IgG isotypes were associated with venous thrombosis and ischaemic cerebrovascular disease, whereas aPLs of IgM isotype were weakly associated with ischaemic heart disease. Associations were greatly affected by aPL level. LA performed better than the specific aPL tests. LA was associated with any thrombotic event, odds ratio 5.4 (95% CI 3.1, 9.4), while the specific aPL tests ranged from non-significant to an odds ratio of 1.9 (95% CI 1.03, 3.4) using criteria cut-off. LA was also convincingly associated with other APS manifestations.

    Conclusion

    In relation to thrombotic manifestations, there was moderate agreement but no clear advantages when comparing a routine aPL ELISA with an automated method. APL isotype and titre as well as LA positivity are important for risk assessment in SLE patients.

  • 929. Virkki, Liisa M
    et al.
    Porola, Pauliina
    Forsblad-d'Elia, Helena
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Valtysdottir, Sigridur
    Solovieva, Svetlana A
    Konttinen, Yrjö T
    Dehydroepiandrosterone (DHEA) substitution treatment for severe fatigue in DHEA-deficient patients with primary Sjögren's syndrome.2010Ingår i: Arthritis care & research, ISSN 2151-4658, Vol. 62, nr 1, s. 118-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Primary Sjögren's syndrome (SS) is characterized by fatigue and low levels of serum dehydroepiandrosterone/dehydroepiandrosterone sulfate (DHEA/DHEAS). Our aim was to study whether SS patients with severe fatigue and low serum DHEAS values benefit from DHEA substitution (50 mg/day).

    METHODS: A multicenter, investigator-based, powered, randomized controlled clinical trial (crossover, washout design) using fatigue as the primary outcome measure was performed on patients with primary SS (n = 107) who had a general fatigue score > or =14 on the 20-item Multiple Fatigue Inventory (MFI-20), combined with age- and sex-adjusted serum DHEAS values below the mean. Fatigue was assessed using MFI-20 subscales, i.e., general fatigue, physical fatigue, mental fatigue, reduced motivation, and activity (scale 4-20), and with a visual analog scale (VAS; scale 0-100).

    RESULTS: In an intent-to-treat analysis, a 50-mg DHEA substitution dose and placebo similarly improved fatigue. All of the MFI-20 subscales and the fatigue VAS improved from the baseline levels as a result of treatment (P < 0.001), but with negligible differences between these 2 treatments. The mean between-treatment difference was -0.1 for general fatigue (the primary outcome measure), 0.0 for physical fatigue, 0.0 for mental fatigue, 0.0 for reduced motivation, 0.3 for reduced activity, and 2.2 for the fatigue VAS. None of these differences was statistically significant.

    CONCLUSION: Similar to earlier results using pharmacologic doses, substitution treatment with 50 mg of DHEA in DHEA-deficient and severely tired primary SS patients does not help against fatigue better than placebo. This may relate to the prohormone nature of DHEA and its recently described defective intracrine tissue-specific conversion to active sex steroids in SS.

  • 930.
    Vultaggio, A.
    et al.
    Careggi Univ Hosp, Dept Biomed, Immunoallergol Unit, Florence, Italy.
    Nencini, F.
    Univ Florence, Ctr Res Transfer & High Educ DENOTHE, Florence, Italy;Univ Florence, Dept Expt & Clin Med, Florence, Italy.
    Carraresi, A.
    Careggi Univ Hosp, Dept Biomed, Immunoallergol Unit, Florence, Italy.
    Pratesi, S.
    Univ Florence, Ctr Res Transfer & High Educ DENOTHE, Florence, Italy;Univ Florence, Dept Expt & Clin Med, Florence, Italy.
    Movérare, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning. Thermo Fisher Sci, ImmunoDiagnost, Uppsala, Sweden.
    Eriksson, C.
    Thermo Fisher Sci, ImmunoDiagnost, Uppsala, Sweden.
    Venemalm, L.
    Thermo Fisher Sci, ImmunoDiagnost, Uppsala, Sweden.
    Maggi, E.
    Univ Florence, Ctr Res Transfer & High Educ DENOTHE, Florence, Italy;Univ Florence, Dept Expt & Clin Med, Florence, Italy.
    Matucci, A.
    Careggi Univ Hosp, Dept Biomed, Immunoallergol Unit, Florence, Italy.
    IgG4 anti-infliximab in treated patients: Clinical impact and temporal evolution2018Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 73, nr 11, s. 2172-2181Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Infliximab (IFX) carries potential risk of immunogenicity with the production of anti-drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti-IFX antibodies in a cohort of IFX-treated patients and to evaluate their relationship with ADA and their clinical impact.

    Methods: Anti-drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti-IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti-IFX.

    Results: IgG4 anti-IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti-IFX. Two IgG4-positive but ADA-negative patients were identified. IgG4 anti-IFX levels correlated with the serum levels of ADA. IgG4 anti-IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE-mediated reactions displayed significantly higher IgG4 anti-IFX than IgE-negative reactive patients. The majority of patients tested positive for IgG4 anti-IFX after the first seven infusions.

    Conclusions: IgG4 anti-IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti-IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti-IFX response.

  • 931. Wadström, H
    et al.
    Eriksson, J K
    Neovius, M
    Askling, J
    How good is the coverage and how accurate are exposure data in the Swedish Biologics Register (ARTIS)?2015Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To assess the coverage of the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden, ARTIS) across indications, and the accuracy of the registered information on treatment with biologics.

    METHOD: Through cross-reference of ARTIS to almost complete national health registers on prescriptions (adalimumab and etanercept), outpatient visits, and death/residency during 2008-2010, we assessed: the treatment coverage of ARTIS for each treatment indication, the validity of the registered start and stop dates, ARTIS treatments with no corresponding drug dispensations, and the accuracy of the registered information on concomitant anti-rheumatic therapies.

    RESULTS: According to the national health registers, 3945 individuals with a spondyloarthropathy (SpA) and 8032 patients with rheumatoid arthritis (RA) had filled at least one adalimumab or etanercept prescription during the study period. Of these, 86% of those with SpAs and 95% of patients with RA were also found in ARTIS with the corresponding treatment. Tumour necrosis factor (TNF) inhibitor prescriptions had been filled by 95% of patients between the ARTIS start and stop dates (allowing a 90-day window). More than 60 days before and more than 60 days after the registered start date in ARTIS, 5% and 4% respectively of patients had filled their first TNF inhibitor prescription. More than 90 days after the registered stop date in ARTIS, 8% of patients had filled one or more TNF inhibitor prescriptions.

    CONCLUSIONS: We observed a high coverage and accuracy of ARTIS data on biologics exposure, for both SpAs and RA. The combination of data from clinical registers such as ARTIS with data from national health registers offers a high quality measurement of actual treatment.

  • 932. Wadström, H
    et al.
    Eriksson, J K
    Neovius, M
    Askling, J
    Baecklund, Eva
    How good is the coverage and how accurate are exposure data in the Swedish Biologics Register (ARTIS)?2015Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To assess the coverage of the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden, ARTIS) across indications, and the accuracy of the registered information on treatment with biologics.

    METHOD: Through cross-reference of ARTIS to almost complete national health registers on prescriptions (adalimumab and etanercept), outpatient visits, and death/residency during 2008-2010, we assessed: the treatment coverage of ARTIS for each treatment indication, the validity of the registered start and stop dates, ARTIS treatments with no corresponding drug dispensations, and the accuracy of the registered information on concomitant anti-rheumatic therapies.

    RESULTS: According to the national health registers, 3945 individuals with a spondyloarthropathy (SpA) and 8032 patients with rheumatoid arthritis (RA) had filled at least one adalimumab or etanercept prescription during the study period. Of these, 86% of those with SpAs and 95% of patients with RA were also found in ARTIS with the corresponding treatment. Tumour necrosis factor (TNF) inhibitor prescriptions had been filled by 95% of patients between the ARTIS start and stop dates (allowing a 90-day window). More than 60 days before and more than 60 days after the registered start date in ARTIS, 5% and 4% respectively of patients had filled their first TNF inhibitor prescription. More than 90 days after the registered stop date in ARTIS, 8% of patients had filled one or more TNF inhibitor prescriptions.

    CONCLUSIONS: We observed a high coverage and accuracy of ARTIS data on biologics exposure, for both SpAs and RA. The combination of data from clinical registers such as ARTIS with data from national health registers offers a high quality measurement of actual treatment.

  • 933.
    Wadström, Hjalmar
    et al.
    Department of Medicine Solna, Karolinska Institutet, Stockholm .
    Arkema, Elizabeth V
    Department of Medicine Solna, Karolinska Institutet, Stockholm.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    Askling, Johan
    Department of Medicine Solna, Karolinska Institutet, Stockholm.
    Simard, Julia F
    Department of Medicine Solna, Karolinska Institutet, Stockholm, Department of Health Research and Policy, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
    Cervical neoplasia in systemic lupus erythematosus: a nationwide study.2017Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56, nr 4, s. 613-619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: The aim was to examine the risk of cervical neoplasia in women with SLE, overall and with respect to treatment, compared with women from the general population.

    METHODS: By linking national Swedish registers, we assembled a cohort including women with SLE (n = 4976) and matched general population comparators (n = 29 703). Two subcohorts of treated SLE patients were defined on the basis of treatment with antimalarials (n = 1942) and other immunosuppressants (AZA, CYC, ciclosporin, MTX, MMF or rituximab; n = 2175). The main outcome was defined as a first cervical neoplasia (dysplasia or cancer) during follow-up. Secondary outcomes were first cervical intraepithelial neoplasia (CIN) 1; first CIN grades 2-3; and first invasive cervical cancer during follow-up (2006-12). Cox regression models estimated relative risks adjusted for age, level of education, health-care utilization, number of children, marital status, family history of cervical cancer and prior cervical screening.

    RESULTS: Based on 121 events of cervical neoplasia during 23 136 person-years among SLE patients, there was an increased risk of any cervical neoplasia compared with the general population [hazard ratio (HR) = 2.12 (95% CI: 1.65, 2.71)]. The risk of CIN 1 [HR = 2.33 (95% CI: 1.58, 3.44)], CIN 2-3 [HR = 1.95 (95% CI: 1.43, 2.65)], but not invasive cervical cancer [HR = 1.64 (95% CI: 0.54, 5.02)], was increased in women with SLE. The subcohort treated with other immunosuppressants was at highest risk of cervical neoplasia.

    CONCLUSION: SLE is a risk factor for cervical neoplasia, in particular for pre-malignant cervical lesions. Among patients with SLE, the risk is higher among those treated with immunosuppresants compared with those treated with antimalarials.

  • 934. Wadström, Hjalmar
    et al.
    Frisell, Thomas
    Sparén, Pär
    Askling, Johan
    Do RA or TNF inhibitors increase the risk of cervical neoplasia or of recurrence of previous neoplasia? A nationwide study from Sweden.2016Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To examine screening patterns and the risk of cervical neoplasia in women with rheumatoid arthritis (RA) treated or not with tumour necrosis factor inhibitors (TNFi).

    METHODS: We performed a nationwide register-based cohort study in Sweden of women with RA who started a first TNFi (n=9629), biologics-naive women with RA (n=34 984) and general population comparators (matched 1:10, n=300 331), followed up from 1999 to 2012. Outcomes were first cytology screening with normal outcome, first ever cervical intraepithelial neoplasia (CIN) grade 1, first ever CIN 2-3 or adenocarcinoma in situ and first ever invasive cervical cancer during follow-up. HRs were assessed through Cox regressions adjusted for age, educational level, prior cervical screens, comorbidities, marital status and prior hospitalisations.

    RESULTS: Biologic-naive women with RA had more screenings (HR 1.08, 95% CI 1.06 to 1.10), were at greater risk of CIN 1 (HR 1.53, 1.23 to 1.89) and CIN 2-3 (HR 1.39, 1.16 to 1.66), but not of invasive cervical cancer (HR 1.09, 0.71 to 1.65) compared with the general population. Patients who initiated TNFi therapy had similar screening patterns (HR 1.01, 0.98 to 1.05), were not at increased risk of CIN 1 (HR 1.23, 0.87 to 1.74), but were at increased risk of CIN 2-3 (HR 1.36, 1.01 to 1.82) and invasive cervical cancer (HR 2.10, 1.04 to 4.23) compared with biologics-naive women with RA. Estimates varied little with successive adjustments, but were attenuated/absent in sensitivity analyses restricted to 2006-2012 and a disease-modifying antirheumatic drugs-treated comparator.

    CONCLUSIONS: Women with RA in general are at elevated risk of cervical dysplasia. Compared with biologics-naive patients, women treated with TNFi are at increased risk of cervical cancer. Whether this increase is causally linked with TNFi could not be fully disentangled.

  • 935.
    Waehrens, Eva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Arbetsterapi.
    Bliddal, H.
    Danneskiold-Samsoe, B.
    Lund, H.
    Fisher, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Arbetsterapi.
    Differences between questionnaire- and interview-based measures of activities of daily living (ADL) ability and their association with observed ADL ability in women with rheumatoid arthritis, knee osteoarthritis, and fibromyalgia2012Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 41, nr 2, s. 95-102Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Although self-report based on questionnaire is the common method to obtain information about activities of daily living (ADL) ability in rheumatic diseases, little is known about the relationship between measures of ADL ability based on questionnaire, interview, and observation. The present study examined whether measures of self-reported ADL ability based on questionnaire and interview yielded different results, determined whether the magnitude of the difference varied among women with rheumatoid arthritis (RA), knee osteoarthritis (OA), and fibromyalgia (FM), and investigated the relationships between self-reported and observed ADL ability. Method: The 47 ADL tasks of the ADL taxonomy were used to evaluate self-reported ADL ability based on questionnaire (ADL-Q) and interview (ADL-I), and the Assessment of Motor and Process Skills (AMPS) was used to obtain measures of observed ADL ability. Results: Participants across diagnostic groups reported significantly more ADL ability based on the ADL-Q than on the ADL-I. Moderate correlations were found between the ADL-Q and ADL-I ability measures. Although low to moderate correlations were seen between measures based on the AMPS ADL motor scale and the ADL-Q and ADL-I, respectively, correlations between measures based on AMPS ADL process scale and ADL-Q and ADL-I were generally low. Overall, there was no difference in how the measures based on the two modes of self-report related to the observed ADL ability measures. Conclusion: Measures of self-reported ADL ability based on either questionnaire or interview have limited relationship to each other or to observed performance of ADL tasks.

  • 936.
    Wahlin, Bengt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Fasth, A. E.
    Karp, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Södergren, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Cd8+cd28- t-lymphocytes are associated with subclinical atherosclerosis in patients with rheumatoid arthritis2017Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, s. 250-250Artikel i tidskrift (Övrigt vetenskapligt)
  • 937.
    Wahlin, Bengt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Innala, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Magnusson, Staffan
    Möller, Bozena
    Smedby, Torgny
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Performance of the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis Is Not Superior to the ACC/AHA Risk Calculator2019Ingår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, s. 130-137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Cardiovascular (CV) risk estimation calculators for the general population do not perform well in patients with rheumatoid arthritis (RA). An RA-specific risk calculator has been developed, but did not perform better than a risk calculator for the general population when validated in a heterogeneous multinational cohort.

    METHODS: In a cohort of patients with new-onset RA from northern Sweden (n = 665), the risk of CV disease was estimated by the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA) and the American College of Cardiology/American Heart Association algorithm (ACC/AHA). The ACC/AHA estimation was analyzed, both as crude data and when adjusted according to the recommendations by the European League Against Rheumatism (ACC/AHA × 1.5). ERS-RA was calculated using 2 variants: 1 from patient and physician reports of hypertension (HTN) and hyperlipidemia [ERS-RA (reported)] and 1 from assessments of blood pressure (BP) and blood lipids [ERS-RA (measured)]. The estimations were compared with observed CV events.

    RESULTS: All variants of risk calculators underestimated the CV risk. Discrimination was good for all risk calculators studied. Performance of all risk calculators was poorer in patients with a high grade of inflammation, whereas ACC/AHA × 1.5 performed best in the high-inflammatory patients. In those patients with an estimated risk of 5-15%, no risk calculator performed well.

    CONCLUSION: ERS-RA underestimated the risk of a CV event in our cohort of patients, especially when risk estimations were based on patient or physician reports of HTN and hyperlipidemia instead of assessment of BP and blood lipids. The performance of ERS-RA was no better than that of ACC/AHA × 1.5, and neither performed well in high-inflammatory patients.

  • 938.
    Wahlin, Bengt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Meedt, T.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Jonsson, F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Karp, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Klinisk fysiologi.
    Henein, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Prediction of coronary artery calcification and association with inflammation in rheumatoid arthritis: a follow-up study2014Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, s. 634-635Artikel i tidskrift (Övrigt vetenskapligt)
  • 939.
    Wahlin, Bengt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Meedt, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Jonsson, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Henein, Michael Y.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Wållberg-Jonsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Coronary Artery Calcification Is Related to Inflammation in Rheumatoid Arthritis: A Long-Term Follow-Up Study2016Ingår i: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, artikel-id 1261582Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. A long-term follow-up of patients with rheumatoid arthritis (RA) to evaluate factors related to coronary artery calcification (CAC). Methods. All 22 eligible patients (4 males/18 females, mean age 65 years, and RA-duration 30-36 years) from the original (baseline; n = 39) study of atherosclerosis were included. Inflammation, cardiovascular risk factors, and biomarkers were measured at baseline. At follow-up 13 years later, CAC was assessed by computed tomography (CT) and the grade of inflammation was measured. Multivariate analysis of differences between patients with low (0-10) and high CAC (>10) was done by orthogonal projection to latent structures (OPLS). Results. Ten patients had CAC 0-10 and 12 had >10 (range 18-1700). Patients with high CAC had significantly higher ESR (24.3 versus 9.9 mm/h) and swollen joint count (2 versus 0). The OPLS models discriminated between patients having high or low CAC. With only baseline variables, the sensitivity was 73% and the specificity 82%. The model that also included inflammatory variables from follow-up had a sensitivity of 89% and a specificity of 85%. Exclusion of baseline intima media thickness and plaque from the latter model modestly reduced the accuracy (sensitivity 80% and specificity 83%). Conclusions. CAC is related to inflammation in patients with RA.

  • 940.
    Wahren, M.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Hedlund, M.
    Karolinska Inst, Stockholm, Sweden..
    Thorlacius, G. E.
    Karolinska Inst, Stockholm, Sweden..
    Ivanchenko, M.
    Karolinska Inst, Stockholm, Sweden..
    Kyriakidis, N.
    Karolinska Inst, Stockholm, Sweden..
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala Univ, Uppsala, Sweden..
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Espinosa, A.
    Karolinska Inst, Stockholm, Sweden..
    Sonesson, S. -E
    Type I IFN System Activation In Newborns Exposed To ANTI-RO/SSA Autoantibodies In Utero2017Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, s. 182-182Artikel i tidskrift (Övrigt vetenskapligt)
  • 941.
    Waldheim, E.
    et al.
    Unit of Rheumatology, Karolinska University Hospital, Huddinge,Stockholm, Sweden & Division of Nursing, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Sweden.
    Elkan, A.-C.
    Unit of Rheumatology, Karolinska University Hospital, Huddinge, Stockholm, Sweden & Department of Medicine, Karolinska Institutet, Huddinge, Sweden & Institute of Environmental Medicine, Karolinska Institutet, Sweden.
    Bergman, Stefan
    Research and Development Centre, Spenshult Hospital, Sweden & Department of Rheumatology, Clinical Sciences, Lund University, Sweden.
    Frostegård, J.
    Institute of Environmental Medicine, Unit of Immunology and Chronic Disease, Karolinska Institutet, Sweden.
    Van Vollenhoven, R.
    Unit of Rheumatology, Karolinska University Hospital, Huddinge, Stockholm, Sweden & Department of Medicine, Karolinska Institutet, Solna, Sweden.
    Henriksson, E. W.
    Unit of Rheumatology, Karolinska University Hospital, Huddinge, Stockholm, Sweden & Division of Nursing, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Sweden.
    Extent and characteristics of self-reported pain in patients with systemic lupus erythematosus2013Ingår i: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 22, nr 2, s. 136-143Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Patients' own experiences of subjective symptoms are scarcely covered, and the objective of this study was to investigate the extent and characteristics of self-reported pain in patients with systemic lupus erythematosus (SLE).

    METHODS: This study comprised a cross-sectional design where 84 patients with SLE were asked to complete self-assessments: visual analogue scale of pain and the Short-Form McGill Pain Questionnaire. Medical assessments, including ESR, SLAM, SLEDAI, and SLICC, were also performed.

    RESULTS: Of the study population, 24% reported higher levels of SLE-related pain (≥40 mm on VAS). This group had a significantly shorter disease duration, higher ESR, and higher disease activity, according to the SLAM and SLEDAI, compared to the rest of the study population. This group mainly used the words "tender," "aching," and "burning" to describe moderate and severe pain, and they used a greater number of words to describe their pain. Of the patients with higher levels of pain, 70% reported their present pain as "distressing." The most common pain location for the whole patient population was the joints. Patients rated their disease activity significantly higher than physicians did.

    CONCLUSION: These findings expand the current knowledge of the extent of SLE-related pain and how patients perceive this pain. The results can contribute to affirmative, supportive and caring communication and especially highlight SLE-related pain in patients with a short disease duration and high disease activity.

  • 942.
    Waldheim, E.
    et al.
    Unit of Rheumatology, Karolinska University Hospital, Sweden & Division of Nursing, Department of Neurobiology, Karolinska Institutet, Sweden.
    Elkan, A.-C.
    Innovation and Development SRQ (Swedish Rheumatology Quality Register), Dept. of Rheumatology, Karolinska University Hospital, Sweden & Institute of Environmental Medicine, Karolinska Institutet, Sweden.
    Pettersson, S.
    Unit of Rheumatology, Karolinska University Hospital, Sweden & Division of Nursing, Department of Neurobiology, Karolinska Institutet, Sweden.
    Van Vollenhoven, R.
    Unit of Rheumatology, Karolinska University Hospital, Sweden & Department of Medicine, Solna, Karolinska Institutet, Sweden.
    Bergman, Stefan
    Research and Development Centre, Spenshult Hospital, Sweden & Department of Rheumatology, Clinical Sciences, Lund University, Sweden.
    Frostegård, J.
    Institute of Environmental Medicine, Unit of Immunology and Chronic Disease, Karolinska Institutet, Sweden.
    Welin Henriksson, E.
    Unit of Rheumatology, Karolinska University Hospital, Sweden & Division of Nursing, Department of Neurobiology, Karolinska Institutet, Sweden.
    Health-related quality of life, fatigue and mood in patients with SLE and high levels of pain compared to controls and patients with low levels of pain2013Ingår i: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 22, nr 11, s. 1118-1127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective The objective of this paper is to investigate health-related quality of life (HRQoL), fatigue, anxiety and depression in patients with systemic lupus erythematosus (SLE) and higher levels of pain and to compare them to patients with lower levels of pain and controls.

    Method Patients were dichotomized into two groups based on SLE-related pain score on the visual analog scale (VAS): low-pain group (76%, n=64, VAS 0-39 mm) and high-pain group (24%, n=20, VAS 40-100 mm). Sex- and age-matched controls were randomly selected from the general population. Participants were asked to complete questionnaires regarding self-reported pain, HRQoL, fatigue, anxiety and depression. Medical assessments also were recorded.

    Result Fatigue score in the high-pain group (median, 36.5; interquartile range (IQR), 32.5-39.7) was significantly higher (p<0.001) compared to the low-pain group (median, 23; IQR, 14.6-34.1), as well as scores for anxiety (median, 9; IQR, 6.5-11.5) and depression (median, 7.5; IQR, 5.5-9) (p<0.001). The high-pain group had significantly lower scores compared to the low-pain group in all dimensions in the SF-36 (p ≤ 0.001-0.007). No statistical differences were detected between the low-pain group and controls in any measurement except for the dimensions physical function, general health, vitality and social function in SF-36.

    Conclusion Patients with SLE scoring higher degrees of pain were burdened with more fatigue, anxiety and depression and lower levels of HRQoL compared to patients with lower levels of pain who did not differ significantly from the general population in most dimensions. These results elucidate the importance of identifying patients with higher degrees of pain who are probably in need of more extensive multidimensional interventions to decrease symptom burden.

  • 943.
    Waldheim, Eva
    et al.
    Karolinska Inst, Sweden.
    Ajeganova, Sofia
    Karolinska Inst, Sweden.
    Bergman, Stefan
    Univ Gothenburg, Sweden; Spenshult Res and Dev Ctr, Sweden; Lund Univ, Sweden.
    Frostegard, Johan
    Karolinska Inst, Sweden.
    Welin, Elisabet
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Variation in pain related to systemic lupus erythematosus (SLE): a 7-year follow-up study2018Ingår i: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 37, nr 7, s. 1825-1834Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that most patients with systemic lupus erythematosus (SLE) reported low degree of SLE-related pain. However, 24% of the patients reported high degree of SLE-related pain, more fatigue, anxiety and depression, and worse health-related quality of life (HRQoL). To explore SLE-related pain, the presence of long-standing widespread pain, and patient-reported outcomes (PROs) after 7 years. Sixty-four out of 84 patients participated in a 7-year follow-up of the original survey and completed the same questionnaires answered at inclusion: pain (VAS 100 mm), fatigue (MAF), HRQoL (SF-36), anxiety and depression (HADS), and, if appropriate, a pain-drawing. Differences between inclusion and follow-up (change) were calculated. The patients with a low degree of SLE-related pain at inclusion reported no changes at follow-up in pain and PROs except for worsening in physical function in SF-36, median change (IQR) 0 (- 10 to 5), p = 0.024. Half of the patients with high degree of pain at inclusion reported decreased pain at follow-up, median change (IQR) 45 (35 to 65), p = 0.021; fatigue, 8 (8 to 17), p = 0.018; anxiety, 4 (1 to 4), p = 0.035; and depression, 4 (2 to 5), p = 0.018 and improvements in most dimensions of SF-36. The remaining half of the patients reported no changes regarding pain and PROs except for a worsening in vitality in SF-36, 20 (15 to 35), p = 0.0018. All patients with remaining high level of pain indicated long-standing widespread pain. After 7 years, a subgroup of patients with SLE reported remaining high level of SLE-related pain and a high symptom burden, including long-standing widespread pain. Such patients require more observant attention to receive appropriate treatment.

  • 944.
    Wandell, Per
    et al.
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden..
    Carlsson, Axel C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden..
    Li, Xinjun
    Lund Univ, Ctr Primary Hlth Care Res, Malmo, Sweden..
    Gasevic, Danijela
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Coll Med & Vet Med, Edinburgh, Midlothian, Scotland..
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Holzmann, Martin J.
    Karolinska Univ Hosp, Dept Emergency Med, Huddinge, Sweden.;Karolinska Inst, Dept Internal Med Solna, Stockholm, Sweden..
    Sundquist, Jan
    Lund Univ, Ctr Primary Hlth Care Res, Malmo, Sweden..
    Sundquist, Kristina
    Lund Univ, Ctr Primary Hlth Care Res, Malmo, Sweden..
    Gout in immigrant groups: a cohort study in Sweden2017Ingår i: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 36, nr 5, s. 1091-1102Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our aim was to study the association between country of birth and incidence of gout in different immigrant groups in Sweden. The study population included the whole population of Sweden. Gout was defined as having at least one registered diagnosis in the National Patient Register. The association between incidence of gout and country of birth was assessed by Cox regression, with hazard ratios (HRs) and 95% confidence intervals (95% CI), using Swedish-born individuals as referents. All models were conducted in both men and women, and the full model was adjusted for age, place of residence in Sweden, educational level, marital status, neighbourhood socio-economic status and co-morbidities. The risk of gout varied by country of origin, with highest estimates, compared to Swedish born, in fully adjusted models among men from Iraq (HR 1.82, 95% CI 1.54-2.16), and Russia (HR 1.69, 95% CI 1.26-2.27), and also high among men from Austria, Poland, Africa and Asian countries outside the Middle East; and among women from Africa (HR 2.23, 95% CI 1.50-3.31), Hungary (HR 1.98, 95% CI 1.45-2.71), Iraq (HR 1.76, 95% CI 1.13-2.74) and Austria (HR 1.70, 95% CI 1.07-2.70), and also high among women from Poland. The risk of gout was lower among men from Greece, Spain, Nordic countries (except Finland) and Latin America and among women from Southern Europe, compared to their Swedish counterparts. The increased risk of gout among several immigrant groups is likely explained by a high cardio-metabolic risk factor pattern needing attention.

  • 945. Wang, C.
    et al.
    Ahlford, A.
    Laxman, N.
    Nordmark, G.
    Eloranta, M-L
    Gunnarsson, I.
    Svenungsson, E.
    Padyukov, L.
    Sturfelt, G.
    Jonsen, A.
    Bengtsson, A. A.
    Truedsson, L.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sjowall, C.
    Sandling, J. K.
    Ronnblom, L.
    Syvanen, A-C
    Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility2013Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 14, nr 4, s. 217-222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value = 1.0 x 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio = 0.56; P-value = 6.6 x 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

  • 946. Wang, Chuan
    et al.
    Kokkonen, Heidi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sandling, Johanna K
    Johansson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Seddighzadeh, Maria
    Padyukov, Leonid
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Syvänen, Ann-Christine
    Preferential association of interferon regulatory factor 5 gene variants with seronegative rheumatoid arthritis in 2 Swedish case-control studies2011Ingår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, nr 10, s. 2130-2132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Two interferon regulatory factor 5 (IRF5) gene variants were examined for association with rheumatoid arthritis (RA).

    Methods: A total of 2300 patients with RA and 1836 controls were recruited from 2 independent RA studies in Sweden. One insertion-deletion polymorphism (CGGGG indel) and one single-nucleotide polymorphism (rs10488631) in the IRF5gene were genotyped and analyzed within RA subgroups stratified by rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA).

    Results: The CGGGG indel was preferentially associated with the RF-negative (OR 1.29, p = 7.9 × 10−5) and ACPA-negative (OR 1.27, p = 7.3 × 10−5) RA subgroups compared to the seropositive counterparts. rs10488631 was exclusively associated within the seronegative RA subgroups (RF-negative: OR 1.24, p = 0.016; ACPA-negative: OR 1.27, p = 4.1 × 10−3).

    Conclusion: Both the CGGGG indel and rs10488631 are relevant for RA susceptibility, especially for seronegative RA.

  • 947. Wang, Ning
    et al.
    Shen, Nan
    Vyse, Timothy J
    Anand, Vidya
    Gunnarson, Iva
    Sturfelt, Gunnar
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Elvin, Kerstin
    Truedsson, Lennart
    Andersson, Bengt A
    Dahle, Charlotte
    Örtqvist, Eva
    Gregersen, Peter K
    Behrens, Timothy W
    Hammarström, Lennart
    Selective IgA deficiency in autoimmune diseases2011Ingår i: Molecular medicine, ISSN 1528-3658, Vol. 17, nr 11-12, s. 1383-Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Selective IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves' disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) based both on our own, recent, large scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the MHC region has been reported. In addition, non-MHC genes, such as IFIH1 and CLEC16A, are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.

  • 948.
    Wang, Wei-Zhou
    et al.
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China; Department of Orthopedics Surgery, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
    Guo, Xiong
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Duan, Chen
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Ma, Wei Juan
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Zhang, Y G
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Xu, P
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Gao, Z Q
    Department of Orthopedics Surgery, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
    Wang, Z F
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Yan, H
    National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an, China.
    Zhang, Y F
    National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an, China.
    Yu, Y X
    Faculty of Public Health, College of Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Xi'an Jiaotong University, Xi'an, China.
    Chen, J C
    Department of Orthopedics Surgery, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Kuopio, Finland.
    Comparative analysis of gene expression profiles between the normal human cartilage and the one with endemic osteoarthritis.2009Ingår i: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 17, nr 1, s. 83-90, artikel-id 18579416Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To investigate the differences in gene expression profiles of adult articular cartilage with endemic osteoarthritis (OA), Kashin-Beck disease (KBD), and the same regions in the normal joint.

    METHODS: The messenger RNA expression profiles of articular cartilage with KBD diagnosed according to "Diagnosing Criteria of Kashin-Beck Disease in China" were compared with the normal cartilage. Total RNA isolated separately from four pairs of the KBD and normal cartilage samples were evaluated by oligonucleotide microarray analysis. The microarray data were confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) amplification and were compared with previously published experiments.

    RESULTS: About 4100 transcripts, which corresponded to 35% of the expressed transcripts, showed >or=twofold differences in expression between the cartilage tissues in pairs. Approximately 2% of the expressed genes (79, 55 genes expressed in KBD>normal; 24 genes expressed in KBD<normal) were commonly expressed in the four pairs of samples. The expression of some genes related to the metabolism, apoptosis, cell proliferation and matrix degradation activity was significantly different in KBD cartilage than in the normal, similar to the findings for genes that inhibit matrix degradation. Comparisons of qRT-PCR data and the previously reported data with the result of gene chips support the validity of our microarray data.

    CONCLUSION: Differences between KBD cartilage and the normal exhibited a similar pattern among the four pairs examined, indicating the presence of common mechanisms mainly including chondrocyte metabolism and apoptosis that contribute to cartilage destruction in KBD.

  • 949.
    Wang, Weizhuo
    et al.
    Department of Orthopedic Surgery, Second Hospital of Xi’an Jiaotong University, Xi'an, China.
    Guo, Xiong
    Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi'an, China.
    Chen, Junchang
    Department of Orthopedic Surgery, Second Hospital of Xi’an Jiaotong University, Xi'an, China.
    Xu, Peng
    Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi'an, China.
    Lammi, Mikko
    Department of Anatomy, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Morphology and phenotype expression of types I, II, III, and X collagen and MMP-13 of chondrocytes cultured from articular cartilage of Kashin-Beck Disease.2008Ingår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, ISSN 0315-162X (Print), 1499-2752 (Online), Vol. 35, nr 4, s. 696-702, artikel-id 18322983Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: We investigated the characteristics of cell morphology and expression of types I, II, III, and X collagen and matrix metalloproteinase-13 (MMP-13) of chondrocytes from articular cartilage of adult patients with Kashin-Beck Disease (KBD) in vitro to understand the pathogenesis in chondrocytes.

    METHODS: Samples of articular cartilage were divided into 2 groups: KBD group (8 samples, 8 cases) and the control (8 samples, 8 cases). KBD patients were diagnosed according to "Pathological Criteria to Diagnose KBD in China." Hyaline cartilage was digested with collagenase into cell suspensions and cultured in monolayers. Chondrocyte ultrastructure was observed by electron microscope at 10th day in vitro. Primary articular chondrocytes were seeded on microscope slides and immunostained on 12th day of cultivation for types I, II, III, and X collagens and MMP-13. Positive findings were counted by light microscopy and confirmed by flow cytometric analyses.

    RESULTS: Considerable amounts of vacuoles and distorted nuclei, as well as thickening and irregular arrangement of collagen fibrils, were seen in the KBD samples by electron microscopy. Types I, III, and X collagen were stained in the KBD, but not in the control cultures. The percentages of positive staining for type II collagen were significantly lower in KBD than those in controls (t col II = -5.54, p < 0.001), and for MMP-13 in the KBD group were significantly higher (t MMP-13 = 3.70, p < 0.01).

    CONCLUSION: Phenotype expressions of types I, II, III, and X collagen and MMP-13 in chondrocytes cultured in vitro were significantly different between the KBD and control cultures, indicating degenerative and hypertrophic changes in chondrocytes of KBD articular cartilage.

  • 950.
    Wang, Yan
    et al.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Lloyd, Katy A.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Eriksson, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Ramsköld, Daniel
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Lundberg, Karin
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Malmström, Vivianne
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Grönwall, Caroline
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Repertoire Studies in Rheumatoid Arthritis Reveal B-Cell Distortions and Baseline Shifts in Unmutated IgG2018Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70Artikel i tidskrift (Övrigt vetenskapligt)
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