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  • Boman, Antonia, 1991- (creator_code:aut_t)
  • Early rheumatoid arthritis : biomarkers and hormonal factors in relation to disease progression
  • 2021
  • swepub:Mat_doctoralthesis_t (swepub:level_scientificother_t)abstract
    • Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, affecting approximately 0.5 to 1% of the adult population. Although the aetiology is not fully known, a complex interaction between genetic, environmental and stochastic factors is thought to trigger the pathogenic mechanisms. A distinguishing feature of RA is the presence of disease associated autoantibodies, mainly rheumatoid factor (RF) and anti-cyclic citrullinated antibodies (ACPA), which are important in both diagnostic and prognostic purpose. The disease is systemic but primarily affects the joints, and can cause irreversible destructions of cartilage and bone, eventually leading to functional disabilities. Moreover, extra-articular features (i.e., symptoms outside the joints) can occur and the patients have an increased risk for comorbidities, predominantly cardiovascular disease. Since the disease is heterogenous, varying from mild to more severe forms, the prognosis can be difficult to predict. Improvements in early diagnosis and identification of patients at risk of a more severe disease course can lead to better outcomes for the patients. The overall aim of this thesis was to evaluate prognostic biomarkers, and to evaluate hormonal and reproductive factors in relation to cardiovascular events (CVE) in patients with newly diagnosed RA (symptoms <12 months).Methods: The patients were included in a prospective inception cohort from the years of 1996 to 2017 and followed-up regularly at the early RA clinics in the northern region of Sweden. Clinical and laboratory parameters, and treatment were regularly recorded in the Swedish Rheumatology Quality Register (SRQ). Enzyme-linked immunosorbent assays (ELISA) and a multiplex assay were used to analyse bone remodelling factors and ACPA reactivities, respectively. Questionnaires regarding hormonal and reproductive factors were sent out to female patients ≤80 years. Information of CVE was extracted from the Swedish National Health Register and Cause of Death Register. Potential markers for disease progression i.e., bone remodelling factors and autoantibodies were analysed in relation to disease progression. Hormonal and reproductive factors were analysed in relation to CVE. Results: In paper I we found associations between receptor activator of nuclear factor kappa-B (RANKL), a central molecule of bone metabolism, and radiological findings at baseline, 24 months, and radiological progression analysed in 407 RA patients. The combination of RANKL and anti-CCP positivity indicated a more severe disease course in terms of joint destruction. Sclerostin was not associated with radiological outcome. Polymorphisms of the genes for sclerostin (SOST) and RANKL (TNFSF11) did not show significant associations with radiological outcome or with the concentrations, respectively. In paper II, we found that even though antibody status is considered in clinical practice and modern treatment reduces disease activity, the radiographic joint damage remained increased among anti-CCP positive patients. In paper III, 22 different ACPA reactivities were analysed in relation to disease courses of RA. The presence of a higher number of different ACPA reactivities, and different ACPA subtypes could provide prognostic information of disease activity and radiological destruction. In paper IV, we found that hormonal and reproductive factors were associated with CVE in female patients. A higher number of childbirths increased the risk for CVE, whilst oral contraceptives decreased the risk. The majority of patients with later CVE had their RA disease onset after menopause and had a longer duration from menopause until RA onset.Conclusion: RANKL can function as a prognostic marker for the disease course of RA. Even though anti-CCP antibodies are taken into account in clinical practice and treatment reduce disease activity, the joint damage can progress, supporting the direct bone degrading effects by ACPA. The number of, and different subtypes of ACPA, can predict different disease progression. These markers can be valuable to identify patients at need for more aggressive treatment and careful radiographic monitoring, even if disease activity is under control. Finally, hormonal factors such as childbirths, oral contraceptives and the timing of RA onset in relation to hormonal status can add value for the evaluation of CVE risk in female RA patients. 
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3.
  • Boman, Antonia, et al. (creator_code:aut_t)
  • Hormonal and reproductive factors in relation to cardiovascular events in women with early rheumatoid arthritis
  • 2023
  • record:In_t: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 12:1
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Hormonal and reproductive factors affect the risk for cardiovascular events (CVE) in the general population. Although the risk of CVE is increased in rheumatoid arthritis (RA), the knowledge about the impact of hormonal factors for CVE in RA is sparse. Female postmenopausal patients ≤80 years with early RA were consecutively included in this observational study (n = 803) between 1 January 1996 until 31 December 2017. Questionnaires regarding hormonal factors were distributed from the index date. Data regarding CVE were obtained from the Swedish National Health Register and Cause of Death Register. Associations between CVE and hormonal factors were analyzed using Cox proportional hazard regression. Of the postmenopausal women, 64 women had a CVE after RA onset. The time period from menopause to RA onset was significantly longer for CVE cases with higher proportion of postmenopausal women. In Cox proportional hazard regression models, years from last childbirth and multiparity were associated with higher CVE risk. Adjustments for traditional risk factors did not affect the results except for hypertension. RA onset after menopause and a longer duration from menopause until onset increased the CVE risk. Multiparity was associated with higher CVE risk whilst oral contraceptives decreased the risk. These results can contribute to identification of high-risk patients for CVE beyond traditional risk factors.
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  • Boman, Antonia, et al. (creator_code:aut_t)
  • Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis
  • 2017
  • record:In_t: Clinical Rheumatology. - : Springer Science and Business Media LLC. - 0770-3198 .- 1434-9949. ; 35:5, s. 1005-1012
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47-0.65) ng/mL compared with female controls 0.49 (0.4-0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings.
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6.
  • Eriksson, Catharina, 1955-, et al. (creator_code:aut_t)
  • Autoantibodies predate the onset of Systemic Lupus Erythematosus in northern Sweden
  • 2011
  • record:In_t: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 13:1, s. R30-
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • INTRODUCTION: Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and those with rheumatoid arthritis, suggesting a gradual development of these diseases. To identify autoantibodies in a Northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.METHODS: The register of patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and with a given date for the onset of symptoms was co-analysed with the register of the Medical Biobank, Umea, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Biobank register. Antibodies against anti- Sjogren's syndrome antigen A (Ro/SSA) (60 and 52 kDa), anti- Sjogren's syndrome antigen B (La/SSB), anti-Smith antibody (Sm), ribonucleoprotein (RNP), scleroderma-70 (Scl-70), anti- histidyl-tRNA synthetase antibody (Jo-1), double-stranded DNA (dsDNA); Centromere protein B and histones were analysed using the anti-nuclear antibody test II (ANA-II) Plus Test System (Athena Multi-Lyte(R)) on a Bio-Plex Array Reader (Luminex200). ANA were analysed using indirect immunofluorescence on Human Epidermal cells-2 (HEp2-cells) at a sample dilution of 1:100.RESULTS: Autoantibodies against nuclear antigens were detected 5.6 (+/- 4.7; mean +/- SD) years before the onset of symptoms and 8.7 (+/- 5.6) years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratio (OR) for anti-dsDNA predicting disease was 18.13 (CI 95%; 3.58-91.84), and for ANA 11.5 (CI 95%; 4.54-28.87). Anti-Ro/SSA antibodies appeared first, 6.6 (+/- 2.5) years prior to symptom onset. The mean number of autoantibodies in pre-diseased individuals was 1.4 and after disease onset 3.1 (P< 0.0005). The time predating disease was shorter, and the number of autoantibodies greater, in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations.CONCLUSIONS: Autoantibodies against nuclear antigens were detected in individuals developing SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.
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7.
  • Innala, Lena, et al. (creator_code:aut_t)
  • Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides
  • 2008
  • record:In_t: Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 35:6, s. 1002-1008
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • OBJECTIVE: To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA).METHODS: The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score.RESULTS: Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), and significantly increased area under the curve (AUC) for DAS28 (p < 0.05), ESR (p < 0.01), C-reactive protein (p < 0.01), and swollen joint count (p = 0.057) compared to those without. Corresponding differences were not found in patients with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression (p < 0.0001-0.01) and radiological outcome (p < 0.0001-0.01) at 24 months were significantly predicted by all ACPA after baseline adjustments. PTPN22 T variant and HLA-DRB1 alleles were not related to radiological progression or inflammatory activity over time.CONCLUSION: Anti-MCV antibodies are associated with a more severe RA disease, as measured by DAS28, ESR, and swollen joint count over time, compared with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression was predicted equally by all 4 autoantibodies.
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  • Johansson, Linda, et al. (creator_code:aut_t)
  • An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis
  • 2017
  • record:In_t: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 56:12, s. 2190-2196
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Objectives: RANK ligand (RANKL) is involved in destruction and osteoporosis in RA. In this study, the relationships between RANKL and ACPA, anti-carbamylated protein antibodies (anti-CarP), cytokines and chemokines were analysed in individuals before the onset of RA symptoms, and their associations with radiological findings at disease onset were assessed.Methods: This was a case-control study performed within the Medical Biobank of Northern Sweden that included 470 pre-symptomatic individuals [334 women and 136 men; mean (S.D.) age 52.3 (9.4) years] using blood samples donated before symptom onset (pre-dating time; 5.0 years) and 96 controls (60 women and 36 men). Plasma was analysed for RANKL (BioVendor, Karasek, Brno, Czech Republic), anti-CCP2 antibodies (Eurodiagnostics, Malmo, Sweden), anti-CarP antibodies (in-house ELISA), ACPA specificities (ISAC-platform, Phadia AB, Uppsala, Sweden) and cytokines/chemokines (Meso Scale Discovery methods, Rockville, MD, USA). Radiographs of hands and feet were graded using the Larsen score.Results: The concentration of RANKL was higher in the pre-symptomatic individuals compared with controls; mean (S.E.M.): 0.50 (0.03) vs 0.22 (0.02) nmol/l (P < 0.001). The concentration increased gradually over time until symptom onset but appeared later than ACPA/RF/anti-CarP antibodies. Positivity for these antibodies yielded higher levels of RANKL compared with seronegativity (P < 0.001). RANKL concentrations were significantly associated with IL-6 and IL-10 concentrations. The combination of positivity for RANKL and anti-CarP antibodies resulted in a higher Larsen score at diagnosis beta = 6.18 (95% CI: 0.93, 11.43; P = 0.022).Conclusion: RANKL concentrations were increased several years before symptom onset for RA, particularly in ACPA/RF/anti-CarP-positive individuals, all detectable earlier than RANKL. Positivity for RANKL and anti-CarP antibodies yielded the highest Larsen score at disease onset.
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