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  • 1.
    Berglin, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Einarsdottir, E
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Influence of female hormonal factors, in relation to autoantibodies and genetic markers, on the development of rheumatoid arthritis in northern Sweden: a case-control study2010In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 39, no 6, p. 454-460Article in journal (Refereed)
    Abstract [en]

    A longer duration of breastfeeding increased the risk of developing RA, especially among individuals seropositive for ACPA or IgM-RF or carrying the PTPN22 1858T variant. Use of OC for ≥ 7 years was associated with a decreased risk.

  • 2.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hormonal and reproductive factors in relation to cardiovascular events in women with early rheumatoid arthritis2023In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 12, no 1, article id 208Article in journal (Refereed)
    Abstract [en]

    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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  • 3.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Sclerostin Are Related to Joint Destruction in Early Rheumatoid Arthritis Unrelated to Polymorphisms of the Genes2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 10, article id 3101Article in journal (Other academic)
  • 4.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis2017In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 35, no 5, p. 1005-1012Article in journal (Refereed)
    Abstract [en]

    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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  • 5.
    Eriksson, Catharina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Johansson, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Autoantibodies predate the onset of Systemic Lupus Erythematosus in northern Sweden2011In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, no 1, p. R30-Article in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Jidell, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides2008In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 35, no 6, p. 1002-1008Article in journal (Refereed)
    Abstract [en]

    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.

  • 7.
    Johansson, L.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kindstedt, Elin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Holm, Cecilia Koskinen
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, I.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, P.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Marginal jawbone loss is associated with onset of rheumatoid arthritis and is related to plasma level of receptor activator of nuclear factor kappa-B ligand2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 22-22Article in journal (Other academic)
  • 8.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis2017In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56, no 12, p. 2190-2196Article in journal (Refereed)
    Abstract [en]

    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.

  • 9.
    Kindstedt, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL2018In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 70, no 4, p. 508-515Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.

    Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.

    Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.

    Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.

  • 10.
    Kindstedt, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Marginal Jawbone Loss Predates the Onset of Rheumatoid Arthritis2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69Article in journal (Other academic)
    Abstract [en]

    Background/Purpose: Previous studies have shown a higher incidence of alveolar bone loss in patients with rheumatoid arthritis (RA) and that patients with periodontitis are at a greater risk for developing RA. Periodontitis, displayed as marginal jawbone loss was analysed in individuals prior to symptom onset of RA and related to plasma levels of receptor activator of nuclear factor kappa-B (RANKL), a cytokine crucial for bone resorption. Methods: A case-control study performed within the Medical Biobank of Northern Sweden included 232 pre-symptomatic individuals with blood samples donated before symptom onset and 194 controls. A questionnaire on self-assed dental status and smoking status was retrieved. Dental radiographs to evaluate marginal jawbone levels were available from 93 pre-symptomatic individuals (mean age; 56.8 95%CI55.9, 57.7 years and pre-dating time; -5.3 95%CI -12.2, -0.2, 74.2% females) and 83 controls (mean age; 55.5 95%CI54.6, 56.5, 73.5% females) . Of these individuals 45 had radiograph documentations prior to development of RA symptoms and to whom sex, age and smoking status could be matched among the controls. Plasma were analysed for RANKL (BioVendor, Karasek, Czech Republic), and anti-citrullinated peptide antibodies (ACPA) (anti-CCP2 test, Eurodiagnostics, Sweden) from similar time points. Results: Compared to matched controls, total bone loss was significantly higher in never-smokers who developed RA but not in smokers and increasing levels on total jawbone loss was associated with a significantly higher odds to be diagnosed with RA later (OR=1.06, 95%CI 1.01, 1.11). Regardless of smoking status, the number of unaffected teeth did not differ significantly between those who were subsequently diagnosed with RA and their matched controls. In the pre-symptomatic individuals RANKL positive individuals had significantly higher extent of marginal jawbone loss, which was further increased in ACPA positive individuals. Previously documented association between smoking and ageing and marginal jawbone loss was verified. Conclusion: Marginal jawbone loss preceded onset of symptoms of RA but the difference was only manifested in non-smokers. Moreover, marginal jawbone loss and plasma RANKL levels were related in the pre-symptomatic individuals particularly in ACPA positive individuals.

  • 11.
    Kindstedt, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 4, p. 508-515Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.

    Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.

    Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.

    Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.

  • 12. Kissel, Theresa
    et al.
    van Schie, Karin Anna
    Hafkenscheid, Lise
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wuhrer, Manfred
    Huizinga, Tom W. J.
    Scherer, Hans Ulrich
    Toes, Rene
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 12, p. 1616-1620Article in journal (Refereed)
    Abstract [en]

    Objective: Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.

    Methods: ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).

    Results: V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.

    Conclusion: Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.

  • 13. Kissel, Theresa
    et al.
    van Schie, Karin
    Hafkenscheid, Lise
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Scherer, Hans Ulrich
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Toes, Rene
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rising ACPA igg variable domain glycosylation pre-disease associates with an increase in autoantibody levels and the development of rheumatoid arthritis2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 249-250Article in journal (Other academic)
    Abstract [en]

    Background: Anti-citrullinated protein antibodies (ACPA) are present in the majority of rheumatoid arthritis (RA) patients (60-70%) and play a pivotal role in disease development1. ACPA IgGs are unique in a way that they are abundantly N-glycosylated within their variable regions2. These variable domain (V-domain) glycans are found on over 90% of ACPAs present in sera from RA-patients3. To undergo N-linked glycosylation, a consensus sequence in the protein backbone is required (N-X-S/T, where X ≠ P)4. Recently, it was shown that the N-linked glycosylation sites in ACPA-IgG V-domains are introduced during somatic hypermutation and that the introduction of such sites likely conveys a selective advantage to ACPA expressing B-cells5. However, it is currently unknown, whether ACPA-expressing B-cells already introduced glycosylation-sites into their V-domains before disease onset or when ACPA-V-domain glycosylation occurs.

    Objectives: Investigate the appearance of ACPA V-domain glycosylation in pre-symptomatic individuals and RA patients.

    Methods In a case-control study, individuals (n=201) from the Medical Biobank, who were sampled before onset of symptoms (mean±SEM predating time; 5.8±0.3 years) (140 aCCP+ and 61 aCCP-), and after diagnosis of RA (n=99, 94 aCCP+ and 5 aCCP-) and randomly selected control samples (n=43, 3 aCCP+ and 40 aCCP-) were analyzed for their ACPA IgG V-domain glycosylation levels. ACPA IgGs were affinity purified, N-linked glycans released, and 2-AA labeled for further analysis using UHPLC6. Data calibration and integration was performed and a cut-off defined. Samples below the cut-off were determined as non-detectable and excluded from the analysis. The percentage V-domain glycosylation was calculated as described previously3. Statistical calculations were performed using SPSS.

    Results: Our data indicated that ACPA IgG V-domain glycans are already present years before symptom onset, in pre-symptomatic individuals who subsequently will develop RA. Analysis of matched pairs showed a significant increase of ACPA V-domain glycosylation in RA patients compared to individuals pre-disease (p<0.001). The results showed that ACPA N-glycosylation was correlated with anti-CCP concentrations pre-disease (rs =0.504, p<0.001), while no such association can be found after RA onset. Further, V-domain glycosylation levels increase closer to symptom onset.

  • 14. Kissel, Theresa
    et al.
    Van Wesemael, Tineke J.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kawakami, Atsushi
    Tamai, Mami
    Van Schaardenburg, Dirkjan
    Wuhrer, Manfred
    Huizinga, Tom W.J.
    Scherer, Hans Ulrich
    Van Der Woude, Diane
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Toes, René E.M.
    Genetic predisposition (HLA-SE) is associated with ACPA-IgG variable domain glycosylation in the predisease phase of RA2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 16, p. 1-3Article in journal (Refereed)
  • 15.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pathogenetic factors of importance for the development and progression of rheumatoid arthritis2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation eventually leading to the destruction of cartilage and bone. The aetiopathogenesis is not completely understood, but previous studies have shown that the disease is multifactorial with genetic, environmental and hormonal factors involved. Immune cells, e.g., T- and B-cells, and macrophages, migrate into the joints, with increased expression of numerous soluble factors such as cytokines, chemokines and adhesion molecules functionally active both locally and systemically. Analyses of blood samples from the Medical Biobank in Umeå from individuals before the onset of symptoms of joint disease showed that anti-citrullinated protein/peptide antibodies (ACPA) preceded the development of disease by years and this finding has been confirmed by other studies.                                        

    The aim of this thesis was to identify signs of activation of the immune system analysed as up-regulation of pro- and anti-inflammatory cytokines, sero-positivity for autoantibodies, and genetic factors identified as relevant for the development and disease progression of RA. The concentrations of 30 cytokines and chemokines were measured in blood samples from individuals before the onset of symptoms, and when diagnosed with RA, together with population-based matched controls using a multiplex system. The predictive value of different isotypes (IgG, IgA, and IgM) of ACPA and rheumatoid factor (RF) before onset of symptoms and different types of ACPA (e.g., mutated citrullinated vimentin, MCV) were analysed for disease development and progression in patients with early RA and controls from Northern Sweden. These factors were related to the genetic markers, HLA- shared epitope (SE) alleles and the 1858C/T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene.                           

    In paper I, it was shown that in individuals who later developed RA (i.e., pre-patients) the levels of several cytokines and related factors that represent the adaptive immune system (Th1, Th2, and T regulatory cell related factors) were significantly elevated compared with controls, whereas, after the onset of disease the involvement of the immune system was more general and widespread. In paper II, the presence of different isotypes (IgM, IgA and IgG) of ACPA in pre-patients, patients and controls was evaluated showing that both the IgG and IgA isotype predicted the onset of RA by years with the IgG isotype having the highest predictive value. In paper III, the association of the 1858T variant of PTPN22 with RA was confirmed. Furthermore, the association was restricted to autoantibody positive disease and this variant was correlated with an earlier age for disease onset. In paper IV, anti-MCV antibodies were identified as being associated with a more severe disease course of RA, measured by disease activity score, erythrocyte sedimentation rate, and swollen joint count over time compared with anti-CCP2, anti-CCP3, and anti-CCP3.1 antibodies.                                                                                               

    In conclusion, individuals who later developed RA had increased concentrations of inflammatory markers reflecting an activation of the immune system years before the clinical symptoms of the disease developed. Also, the presence of ACPA of IgG and IgA isotype prior to disease onset predicted the development of RA. The PTPN22 1858T variant was associated with sero-positive RA and anti-MCV antibodies were associated with a higher inflammatory activity compared with anti-CCP2, -CCP3 and -CCP3.1 antibodies. These findings together present a possibility to better predict the development and progression of RA.

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    Pathogenetic Factors of Importance for the Development and Progression of Rheumatoid Arthritis
  • 16.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hansson, Monika
    Stockholm, Sweden.
    Lassen, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mathsson-Alm, Linda
    Uppsala, Sweden.
    Holmdahl, Rikard
    Stockholm, Sweden.
    Rönnelid, Johan
    Uppsala, Sweden.
    Klareskog, Lars
    Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 125Article in journal (Refereed)
    Abstract [en]

    Introduction: It has previously been shown that an increased number of antibodies against citrullinated peptides/proteins (ACPA) predate the onset of rheumatoid arthritis (RA). Over time antibody positivity expands, involving more specific responses when approaching the onset of symptoms. We investigated the impact of human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking on the development of ACPA, as well as in combination with ACPA during the state of quiescent autoimmunity (before the onset of symptoms), on the development of RA. Methods: Blood samples donated to the Medical Biobank of Northern Sweden from individuals prior to the onset of symptoms of RA (n = 370) and after onset (n = 203) and from population-based controls (n = 585) were used. Antibodies against 10 citrullinated peptides, fibrinogen (Fib alpha 561-583, alpha 580-600, beta 62-81a, beta 62-81b, beta 36-52), vimentin (Vim2-17, 60-75), filaggrin (CCP-1/Fil307-324),alpha-enolase (CEP-1/Eno5-21), collagen type II (citC1359-369), and anti-cyclic citrullinated peptide (CCP) 2 antibodies were analysed. Results: HLA-SE-positive individuals were more frequently positive for ACPA compared with HLA-SE-negative individuals prior to the onset of symptoms of RA, particularly for antibodies against CEP-1 and Fib beta 62-81a (72). Smoking was associated with antibodies against Vim2-17 and citC1359-369. HLA-SE and smoking showed increasing association to the presence of the antibodies closer to disease onset. The highest odds ratio (OR) for development of RA was for the combination of HLA-SE alleles and ACPA positivity, especially for antibodies against Fib beta 62-81b, CCP-1/Fil307-324, and Fib beta 36-52. A gene-environment additive interaction between smoking and HLA-SE alleles for the risk of disease development was found, with the highest OR for individuals positive for antibodies against Fib beta 36-52, CEP-1, and Fib alpha 580-600. Conclusions: The relationships between antibodies against the different ACPA specificities, HLA-SE, and smoking showed a variable pattern in individuals prior to the onset of RA. The combination of smoking and HLA-SE alleles was significantly associated with the development of some of the antibody specificities closer to onset of symptoms, and these associations remained significant at diagnosis. An additive gene-environment interaction was found for several of the antibodies for the development of RA.

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  • 17.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Brink, Mikael
    Hansson, Monika
    Mathsson, Linda
    Lassen, Ewa
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Ronnelid, Johan
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt M.
    Interaction of Antibodies Against Citrullinated Peptides with HLA Shared Epitope, PTPN22 1858T Variant, and Smoking in Individuals Prior to and After the Development of Rheumatoid Arthritis.2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. S190-S190Article in journal (Other academic)
  • 18.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Cardiovascular risk factors before onset of rheumatoid arthritis are associated with cardiovascular events after disease onset: a case–control study2022In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, no 21, article id 6535Article in journal (Refereed)
    Abstract [en]

    Background: The increased comorbidity and mortality in rheumatoid arthritis (RA) patients are largely due to cardiovascular disease (CVD). Previously, we demonstrated increased frequencies of risk factors for CVD (elevated body mass index (BMI), elevated apoliprotein (Apo) B:ApoA1 ratio, and smoking) in pre-RA individuals compared with matched controls. Objectives: Assess the impact of traditional CV risk factors present before the onset of RA on the risk of CV events (CVE) after diagnosis in comparison with matched controls. Methods: A case–control study including 521 pre-symptomatic individuals and 1566 controls identified within the Health Surveys of the Medical Biobank was performed. CVD risk factors were hypertension, elevated ApoB:A1 ratio, BMI, diabetes, and smoking. Information on comorbidities was requested from the Swedish National Patient Register and Cause of Death Register. Results: Pre-RA individuals had a higher risk of future CVE compared with matched controls (HR [95% CI] 1.70 [1.31–2.21]), which remained after adjustments for risk factors for CVD (HR [95% CI] 1.73 [1.27–2.35]). Most risk factors were associated with CVE after diagnosis, and a combination resulted in a higher risk in RA compared with controls; two risk factors, HR [95% CI] 2.70 [1.19–6.13] vs. 1.26 [0.75–2.13]; and three to four risk factors, HR [95% CI] 6.32 [2.92–13.68] vs. 3.77 [2.34–6.00]. Conclusions: Risk factors for CVD present in pre-RA individuals were associated with future CVE, and even after adjustments for these risk factors and treatments after RA onset, pre-RA individuals had a higher risk of CVE compared with controls. These findings further highlight the importance of the early assessment of risk for CVD.

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  • 19.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Inflammatory Markers in Relation to Risk Factors for Cardiovascular Disease in the Pre-Symptomatic Phase of Rheumatoid Arthritis2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69Article in journal (Other academic)
    Abstract [en]

    Background/Purpose: Individuals who later developed rheumatoid arthritis (RA) have increased levels and frequencies of risk factors for cardiovascular disease (CVD), years before onset of RA. The relationships between CVD risk factors and inflammatory markers, i.e., cytokines and chemokines, were analysed in individuals prior to onset of symptoms and compared with controls. Methods: A case-control study was based on population surveys from The Västerbotten Intervention Programme (VIP) and the WHO Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) with data collected on socioeconomic and lifestyle factors, BMI, waist, blood pressure, and blood samples by a nurse. The register of patients with RA (ARA criteria) was co-analysed with the registers from the Medical Biobank and 469 pre-symptomatic individuals (median age 50.2 years; 67.8% women, median predating time 5.0 (IQR; 2.0-8.0) years), and 234 controls (median age 50.3 years; 67.1% women) were identified. CVD risk factors were defined as: hypertension (treatment or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg), elevated ApoB/ApoA1 ratio (women ≥0.7, men ≥0.8, including lipid lowering treatment), BMI ≥25kg/m2, diabetes, and ever being smoker. Concentrations of eotaxin, interferon gamma-induced protein (IP-10), monocyt-chemoattractant protein 1 (MCP1), macrophage derived chemokine (MDC), interleukin (IL) 2, IL-4, IL-6, IL-8, and IL-10, were analysed in plasma using R&D systems' assays (Minneapolis, MN) according to the manufacturer's instructions. Results: Pre-symptomatic individuals had significantly higher levels of IL-6 compared with controls, both in women and men. IL-10 was significantly higher in pre-symptomatic men compared with controls. Cytokines/chemokines were significantly associated with the CVD risk factors in the cases e.g. IL-6 with each of the risk factors, eotaxin with smoking, IP-10 with increased BMI, being diabetes or having hypertension, whilst MDC was associated significantly with smoking and BMI≥25 kg/m2. After adjustments for sex and age only eotaxin concentrations were significantly associated with being ever smoker. In women, MDC was significantly associated with smoking, BMI≥25 kg/m2 and diabetes. Having the combination of several CVD risk factors was associated with significantly higher concentrations of MCP-1, MDC, and IL-6 in pre-symptomatic women. IL-6 increased further the relative risk in combinations with all CVD risk factors for the pre-symptomatic cases compared with controls. Conclusion: Increased concentrations of cytokines/chemokines were associated with CVD risk factors to a higher extent among the pre-symptomatic RA cases compared with controls. The pattern of association varied between the risk factors and the sex of the cases.

  • 20.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Martin
    Dahlqvist, Solbritt Rantapää
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    PTPN22 polymorphism in RA2008In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 37, no Suppl 123, p. 19-19Article in journal (Refereed)
  • 21.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Johansson, Martin
    Innala, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Jidell, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden2007In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 9, no 5, p. 403-Article in journal (Refereed)
    Abstract [en]

    The PTPN22 1858C/T polymorphism has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have shown that carriage of the T variant (CT or TT) of PTPN22 in combination with anti-cyclic citrullinated peptide (anti-CCP) antibodies highly increases the odds ratio for developing RA. In the present study we analysed the association between the PTPN22 1858C/T polymorphism and early RA in patients from northern Sweden, related the polymorphism to autoantibodies and the HLA-DR shared epitope, and analysed their association with markers for disease activity and progression. The inception cohort includes individuals who also donated samples before disease onset. A case-control study was performed in patients (n = 505; 342 females and 163 males) with early RA (mean duration of symptoms = 6.3 months) and in population-based matched controls (n = 970) from northern Sweden. Genotyping of the PTPN22 1858C/T polymorphism was performed using a TaqMan instrument. HLA-shared epitope alleles were identified using PCR sequence-specific primers. Anti-CCP2 antibodies were determined using enzyme-linked immunoassays. Disease activity (that is, the number of swollen and tender joints, the global visual analogue scale, and the erythrocyte sedimentation rate) was followed on a regular basis (that is, at baseline and after 6, 12, 18 and 24 months). Both the 1858T allele and the carriage of T were associated with RA (chi2 = 23.84, P = 0.000001, odds ratio = 1.69, 95% confidence interval = 1.36-2.11; and chi2 = 22.68, P = 0.000002, odds ratio = 1.79, 95% confidence interval = 1.40-2.29, respectively). Association of the 1858T variant with RA was confined to seropositive disease. Carriage of 1858T and the presence of anti-CCP antibodies was independently associated with disease onset at an earlier age (P < 0.05 and P < 0.01, respectively), while the combination of both resulted in an even earlier age at onset. Smoking was identified as a risk factor independent of the 1858T variant and anti-CCP antibodies.

  • 22.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mullazehi, Mohammed
    Division of Clinical Immunology, Uppsala University, 751 85 Uppsala, Sweden.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rönnelid, Johan
    Division of Clinical Immunology, Uppsala University, 751 85 Uppsala, Sweden.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis2011In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, no 1, p. R13-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: We and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease. Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score.

    METHODS: A case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden. Patients with RA were identified from blood donors predating the onset of disease by years. Matched controls were selected randomly from the same registers. IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden).

    RESULTS: Of 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses. The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years). The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM. The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls. IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3. Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP. IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals.

    CONCLUSIONS: Anti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies.

  • 23.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Cardiovascular risk factors predate the onset of symptoms of rheumatoid arthritis: a nested case-control study2017In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, article id 148Article in journal (Refereed)
    Abstract [en]

    Background: Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD). Our aim was to evaluate the impact of factors related to CVD, such as smoking, lipid levels, hypertension, body mass index (BMI) and diabetes, in individuals prior to the onset of symptoms of RA. Methods: A nested case-control study was performed including data from 547 pre-symptomatic individuals (i.e. individuals who had participated in population surveys in northern Sweden prior to onset of symptoms of RA, median time to symptom onset 5.0 (interquartile range 2.0-9.0) years) and 1641 matched controls. Within the survey, health examinations prior to symptom onset were performed, blood samples were analysed for plasma glucose and lipids, and data on lifestyle factors had been collected with a questionnaire. CVD risk factors were extracted and further analysed with conditional logistic regression models for association with subsequent RA development, including hypertension, apolipoprotein (Apo) B/ApoA1 ratio, BMI, diabetes and smoking habits. Results: Smoking and BMI >= 25 (odds ratio (OR) (95% confidence interval (CI)) = 1.86 (1.48-2.35) and OR = 1.28 (1.01-1.62), respectively) were associated with increased risk for future RA development. In women, elevated ApoB/ApoA1 ratio (OR = 1.36 (1.03-1.80)) and smoking (OR = 1.82 (1.37-2.41)) were significantly associated with being pre-symptomatic for RA, whilst in men smoking (OR = 1.92 (1.26-2.92)) and diabetes (OR = 3.62 (95% CI 1.13-11.64)) were significant. In older (> 50.19 years) individuals, only smoking (OR = 1.74 (1.24-2.45)) was significantly associated with increased risk of future RA, whereas in younger individuals the significant factors were elevated ApoB/ApoA1 ratio (OR = 1.39 (1.00-1.93)), BMI >= 25.0 (OR = 1.45 (1.04-2.02)) and smoking (OR = 2.11 (1.51-2.95)). Pre-symptomatic individuals had a higher frequency of risk factors: 41.5% had >= 3 compared with 30.4% among matched controls (OR = 2.81 (1.78-4.44)). Conclusions: Several risk factors for CVD were present in pre-symptomatic individuals and significantly associated with increased risk for future RA. These factors differed in women and men. The CVD risk factors had a greater impact in younger individuals. These results urge an early analysis of cardiovascular risk factors for proposed prevention in patients with early RA.

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  • 24.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 2, p. 383-391Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).

    METHODS: A nested case-control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.

    RESULTS: The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1beta [IL-1beta], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-gamma, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1alpha). The levels were particularly increased in anti-cyclic citrullinated peptide antibody- and rheumatoid factor-positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell-related cytokines, while chemokines, stromal cell-derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA.

    CONCLUSION: Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.

  • 25.
    Sundström, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Johansson, Gunnar
    School of social and health sciences, Halmstad university, Halmstad, Sweden.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Cederholm, Tommy
    Division of clinical nutrition and metabolism, department of public health and caring science, Uppsala university, Uppsala, Sweden.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Plasma phospholipid fatty acid content is related to disease activity in ankylosing spondylitis2012In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 39, no 2, p. 327-333Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the fatty acid composition in the diet, plasma phospholipids, and adipose tissue among a cohort of patients with ankylosing spondylitis (AS), and to determine their correlation to disease activity and blood lipids in a cross-sectionally designed study.

    Methods: Diet was assessed using a food frequency questionnaire on 66 patients with AS. The polyunsaturated fatty acids (PUFAs) in plasma phospholipids and gluteal adipose tissue were measured using gas chromatography. Disease status was quantified using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein and pro-inflammatory cytokines.

    Results: Diet did not correlate to disease activity assessed by the BASDAI, but there were negative correlation between the dietary intake of long-chained omega-3 fatty acids and ESR (rs=-0.27, p<0.05). The plasma phospholipid content of arachidonic acid (AA) correlated significantly with the BASDAI score (rs=0.39, p<0.01). There were correlations between the intake of long-chained omega-3 fatty acids and high-density lipoproteins as well as to serum triglycerides (rs=0.26 and rs=-0.25; respectively, p<0.05).

    Conclusion: There was a positive correlation between levels of AA in plasma phospholipids and disease activity assessed by BASDAI in patients with AS. A western diet does not appear to influence this correlation, but seems to affect blood lipids involved in atherogenic processes. 

  • 26. Wang, Chuan
    et al.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sandling, Johanna K
    Johansson, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Seddighzadeh, Maria
    Padyukov, Leonid
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Syvänen, Ann-Christine
    Preferential association of interferon regulatory factor 5 gene variants with seronegative rheumatoid arthritis in 2 Swedish case-control studies2011In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, no 10, p. 2130-2132Article in journal (Refereed)
    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.

  • 27.
    Ärlestig, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mullazehi, Mohammed
    Department of Immunology, Genetics and Pathology, Uppsala University.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rönnelid, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 825-829Article in journal (Refereed)
    Abstract [en]

    Background Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.

    Objective To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.

    Methods 51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.

    Results The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.

    Conclusions All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

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