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  • 1. Almehed, K
    et al.
    Forsblad d'Elia, Helena
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg.
    Kvist, G
    Ohlsson, C
    Carlsten, H
    Prevalence and risk factors of osteoporosis in female SLE patients-extended report.2007In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 46, no 7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine the frequency of osteoporosis and possible risk factors of low bone mineral density (BMD) in women with systemic lupus erythematous (SLE) in western Sweden. In addition, to evaluate if adequate anti-osteoporotic treatment was provided.

    METHODS: BMD was measured at radius, lumbar spine and hip by dual X-ray absorptiometry (DXA). An 'expected' control BMD was calculated for each patient. Simple and multiple linear regression analyses were performed to determine associations between BMD and demographic and disease-related variables.

    RESULTS: One hundred and sixty-three women were included. Median age was 47 (20-82) yrs, 89 (55%) were post-menopausal and 85 (52%) were taking glucocorticosteroids. BMD was significantly reduced in all measured sites compared with expected BMD. Thirty-seven (23%), 18 (11%) and 6 (4%) of the patients were osteoporotic in at least one, two and three or more measured locations. Bisphosphonates were used by 23 (27%) of patients taking glucocorticosteroids and 13 (35%) with osteoporosis. High age and low weight or BMI were associated with low BMD in all measured sites. In total hip, high SLICC/American Collage of Rheumatology (ACR), ESR and 'combinations of DMARD' were additional markers of low BMD. High S-creatinine was associated with low BMD in lumbal spine whereas high S-creatinine and CRP were markers in radius.

    CONCLUSION: Women with SLE are at greater risk of osteoporosis compared with controls and few are treated adequately. Factors associated with low BMD in SLE are high age and low weight but also markers of inflammation, impaired kidney function and disease damage, however glucocorticosteroids were not associated.

  • 2.
    Berglin, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lorentzon, Ronnie
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordmark, L
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nilsson-Sojka, Birgitta
    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.
    Predictors of radiological progression and changes in hand bone density in early rheumatoid arthritis2003In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 42, no 2, p. 268-275Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify predictors for radiological and functional outcome and bone loss in the hands in early rheumatoid arthritis (RA) during the first 2 yr of disease and to study the relationship between these variables.

    METHODS: An inception cohort of consecutively recruited patients was examined at baseline and after 12 and 24 months using X-rays of hands and feet, clinical [28-joint count, Health Assessment Questionnaire (HAQ), global visual analogue scale (VAS), grip strength] and laboratory (erythrocyte sedimentation rate, C-reactive protein, markers of bone formation and resorption) measurements and dual-energy X-ray absorptiometry measurements of the hands.

    RESULTS: Joint destruction increased significantly during the study, with the Larsen score at baseline as the strongest predictor. Radiological progression and bone loss over 24 months were significantly retarded in patients responding to therapy. The effects of the shared epitope and initial high inflammatory activity on radiological progression were overridden by the therapeutic response. Radiological progression correlated significantly with bone loss. Global VAS, Larsen score and HAQ at inclusion significantly predicted change in HAQ over time.

    CONCLUSIONS: Radiological progression and bone loss were retarded by early therapeutic response. Bone loss was related to radiological progression.

  • 3. Bodman-Smith, M.D.
    et al.
    Corrigall, V.M.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Cornell, H.R.
    Tzioufas, A.G.
    Mavragani, C.P.
    Chan, C.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Panayi, G.S.
    Antibody response to the human stress protein BiP in rheumatoid arthritis2004In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 43, no 10, p. 1283-1287Article in journal (Refereed)
    Abstract [en]

    Objectives. The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA.

    Methods. An ELISA was developed that detected antibodies to BiP. The prevalence of anti-BiP antibodies was determined in sera from patients with early and established RA, sera antedating the onset of RA and sera from patients with other inflammatory and autoimmune diseases and healthy controls.

    Results. We have confirmed the increased prevalence of antibodies to BiP in the sera of a large cohort of patients with established RA (specificity 71% and sensitivity 73%) and early RA (specificity 65% and sensitivity 66%). In pre-disease sera, median 2.5 yr (interquartile range 1.1–4.7) before symptoms of joint disease, the sensitivity for anti-BiP antibodies was 45% and the specificity was 65% for the development of RA.

    Conclusion. Antibodies to BiP are found in the sera of patients with RA and in sera antedating the onset of RA.

  • 4. Burgers, Leonie E.
    et al.
    Siljehult, Filip
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    ten Brinck, Robin M.
    van Steenbergen, Hanna W.
    Landewé, Robert B. M.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    van der Helm-van Mil, Annette H. M.
    Validation of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis2017In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56, no 12, p. 2123-2128Article in journal (Refereed)
    Abstract [en]

    Objectives. Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. Methods. The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umea university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development < 2 years' follow-up. Results. CSA patients with a positive definition (>= 3/7 parameters present) had an increased risk for developing arthritis compared with definition-negative CSA patients (hazard ratio = 2.1, 95% CI: 0.9, 4.7). The sensitivity was 84% and the positive predictive value 30%. In arthralgia patients in whom the definition was applied before rheumatological evaluation, a positive definition was neither sensitive (10%) nor predictive (positive predictive value 3%). Conclusion. The EULAR definition of arthralgia suspicious for progression to RA is sensitive when used to support the rheumatologist's opinion on imminent RA. This validation study shows that the definition, when used as designed, further homogenizes patients that rheumatologists consider at risk for RA. To arrive at a high specificity, the clinical definition needs to be combined with biomarkers.

  • 5. Cvetkovic, J T
    et al.
    Wallberg-Jonsson, S
    Ahmed, E
    Rantapää-Dahlqvist, Solbritt
    Lefvert, A K
    Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis2002In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 41, p. 988-995Article in journal (Refereed)
    Abstract [en]

    Objectives. To analyse the association of autoantibodies against cardiolipin (CL) and oxidized low density lipoproteins [copper-oxidized low density lipoprotein (oxLDL), malondialdehyde-modified LDL (MDA-LDL)] with rheumatoid arthritis (RA) and cardiovascular complications. Methods. One hundred and twenty-one patients with RA were consecutively included. Autoantibodies were determined by ELISA. Healthy individuals from the same region were used as controls. Results. Levels of IgG, IgM and IgA antibodies against MDA-LDL and CL, as well as IgG and IgA antibodies against oxLDL were increased in the patients (P<0.01). The prevalence of IgG, IgM and IgA antibodies against CL was higher than in the normal population (74, 82 and 14%, respectively). The prevalence of IgG and IgA antibodies against oxLDL was also significantly increased (35 and 25%, respectively) and so was the prevalence of IgG and IgM antibodies against MDA-LDL (17 and 26%, respectively) compared with controls. The levels of IgM and IgA antibodies against aCL and IgM against MDA-LDL were increased in patients with extra-articular manifestations. Patients who developed myocardial infarction had a higher prevalence of IgG antibodies against MDA-LDL (P=0.04). There were substantial correlations between the levels of antibodies against oxLDL, MDA-LDL and CL. Conclusions. RA patients had increased levels and prevalence of autoantibodies against CL, oxLDL and MDA-LDL, with associations to severity of disease and cardiovascular complications.

  • 6. Engvall, Inga-Lill
    et al.
    Svensson, Björn
    Boonen, Annelies
    van der Heijde, Désirée
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hafström, Ingiäld
    Low-dose prednisolone in early rheumatoid arthritis inhibits collagen type I degradation by matrix metalloproteinases as assessed by serum 1CTP--a possible mechanism for specific inhibition of radiological destruction2013In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 52, no 4, p. 733-742Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the effects of low-dose prednisolone on the osteoclast-regulating proteins osteoprotegerin (OPG) and RANK ligand (RANKL) and on markers of bone resorption, 1CTP generated by MMPs and CTX-1 generated by cathepsin K, in patients with early RA in relation to inflammation and joint destruction.

    METHODS: In 225 patients, who at the start of the first DMARD had been randomized to 7.5 mg prednisolone daily for 2 years, the P-group, or no prednisolone, the NoP-group, OPG and RANKL were analysed at 0-24 months and 1CTP and CTX-1 at 0-12 months. Radiographs of hands and feet were assessed at 0, 1 and 2 years using the modified Sharp-van der Heijde score and radiological progression defined as increase in total Sharp score above 5.8. Data were analysed with a mixed linear model and by the GENMOD procedure.

    RESULTS: In the P-group, RANKL and the ratio OPG/RANKL were stable between baseline and 24 months, whereas in the NoP-group, RANKL increased and the ratio OPG/RANKL decreased. CTX-1 decreased significantly more in the P-group. 1CTP decreased over time in both groups, but more in the P-group, P < 0.001, a difference also present in the subgroups of patients in remission. The decrease in 1CTP was associated with less radiological progression after 2 years and displayed a significant interaction with treatment. CONCLUSION: Low-dose prednisolone may inhibit progression of joint destruction by interfering with MMP activity, seen as a marked decrease in 1CTP, as well as by impairing osteoclast activation, shown by a stable OPG/RANKL ratio.

  • 7. Eyre, Steve
    et al.
    Bowes, John
    Barton, Anne
    Amos, Chris
    Diogo, Dorothee
    Lee, Annette
    Padyukov, Leonid
    Stahl, Eli A.
    Martin, Javier
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Raychaudhuri, Soumya
    Plenge, Robert
    Klareskog, Lars
    Gregersen, Peter
    Worthington, Jane
    Fine mapping in over 14,000 rheumatoid arthritis cases and 18,500 controls refines associations to known loci, indicates multiple independent affects and reveals novel associations2012In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 51, p. 50-50Article in journal (Other academic)
  • 8.
    Forsblad d'Elia, Helena
    et al.
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg.
    Pullerits, R
    Carlsten, H
    Bokarewa, M
    Resistin in serum is associated with higher levels of IL-1Ra in post-menopausal women with rheumatoid arthritis.2008In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, no 7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of this study was to investigate associations between serum levels of resistin, an adipokine and markers of inflammation, bone metabolism, plasma lipids and kidney function in post-menopausal RA patients and to evaluate if HRT during 2 yrs affected resistin levels.

    METHODS: Eighty-eight women were randomly allocated to receive HRT, vitamin D(3) and calcium or vitamin D(3) and calcium alone. Serum levels of resistin, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-6 soluble receptor, TNF-alpha were measured by ELISA, markers of bone metabolism, carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and carboxyterminal propeptide of type I procollagen by RIA, ESR, CRP, Hb, creatinine and lipids by standard laboratory techniques, BMD and total lean mass (TLM) by DXA and joint destruction by Larsen score. Resistin was also measured in 42 healthy control women.

    RESULTS: There was no difference in resistin concentration between patients and healthy controls. Resistin was significantly correlated with IL-1Ra, CRP, TNF-alpha, ICTP, glucocorticosteroids and Larsen score and inversely with BMD, hip and with TLM. In multiple regression analysis, IL-1Ra, TLM and use of corticosteroids remained determinants of resistin. Patients treated with HRT displayed significant increase in resistin compared with controls in the first but not the second year.

    CONCLUSIONS: Resistin was associated with increased inflammation, particularly by the acute-phase reactant IL-1Ra antagonizing IL-1beta, joint destruction, glucocorticosteroids and with reduced BMD and TLM. These findings suggest resistin being a significant mediator in the inflammatory process in RA. Further studies examining the mechanisms behind the relation between resistin and IL-1Ra are encouraged. HRT does not seem to have important long-term effect on resistin.

  • 9.
    Forsblad-d'Elia, Helena
    et al.
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg.
    Bengtsson, Karin
    Kristensen, Lars Erik
    Jacobsson, Lennart T H
    Drug adherence, response and predictors thereof for tocilizumab in patients with rheumatoid arthritis: results from the Swedish biologics register.2014In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate drug adherence, clinical response and predictors thereof for tocilizumab in patients with RA in routine care based on prospectively collected data from the Swedish biologics register, Anti-Rheumatic Therapies in Sweden.

    METHODS: RA patients who had started with tocilizumab from September 2008 until March 2012 were identified. Cox regression and logistic regression models were used.

    RESULTS: A total of 530 RA patients were included, of whom 80.6% were female, 64.7% were on concomitant DMARDs, of which 300 were on MTX and 12% were biologic naive. The overall 6 month, 1 and 2 year estimated drug continuations were 79%, 64% and 50%, respectively. In the multivariate analyses, a low initial level of CRP [hazard ratio (HR) 0.76/1s.d. (95% CI 0.63, 0.91)], high HAQ score [HR 1.23/1s.d. (95% CI 1.06, 1.44)] and prior exposure to different biologics [HR 1.43 (95% CI 1.12, 1.83)] were predictors for drug termination, whereas concomitant DMARD therapy was not. European League Against Rheumatism (EULAR) good, moderate, and no response were achieved by 184 (46.7%), 133 (33.8%) and 77 (19.5%) patients, respectively. Predictors for EULAR good response vs no response (at 2.5-8 months) were low HAQ [odds ratio (OR) 0.56/1s.d. (95% CI 0.40, 0.78)], high 28-joint DAS [OR 2.0/1s.d. (95% CI 1.44, 2.78)] and not being on prednisolone [OR 0.47 (95% CI 0.25, 0.88)] at baseline.

    CONCLUSION: In this RA cohort treated with tocilizumab, the estimated 1 year drug continuation was 64% and 80% of the patients achieved a EULAR response. Drug discontinuation was not predicted by no concomitant DMARD, but by low CRP, high HAQ and prior exposure to biologics.

  • 10.
    Hager, Charlotte
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Changes in sensorimotor behaviour with pain and how to capture these in a movement analysis laboratory2012In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 51, p. 14-15Article in journal (Other academic)
  • 11. Jiang, Xia
    et al.
    Kallberg, Henrik
    Chen, Zuomei
    Ärlestig, Lisbeth
    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.
    Davila, Sonia
    Klareskog, Lars
    Padyukov, Leonid
    Alfredsson, Lars
    An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis2016In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, no 1, p. 149-155Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the gene–environment interaction between smoking and single nucleotide polymorphisms (SNPs), using Immunochip material, on the risk of developing either of two serologically defined subsets of RA.

    Methods: Interaction between smoking and 133 648 genetic markers from the Immunochip was examined for two RA subsets, defined by the presence or absence of ACPA. A total of 1590 ACPA-positive and 891 ACPA-negative cases were compared with 1856 controls in the Swedish Epidemiological Investigation of RA (EIRA) case–control study. Logistic regression models were used to determine the presence of interaction. The proportion attributable to interaction was calculated for each smoking–SNP pair. Replication was carried out in an independent dataset from northern Sweden. To further validate and extend the results, interaction analysis was also performed using genome-wide association studies data on EIRA individuals.

    Results: In ACPA-positive RA, 102 SNPs interacted significantly with smoking, after Bonferroni correction. All 102 SNPs were located in the HLA region, mainly within the HLA class II region, 51 of which were replicated. No additional loci outside chromosome 6 were identified in the genome-wide association studies validation. After adjusting for HLA-DRB1 shared epitope, 15 smoking–SNP pairs remained significant for ACPA-positive RA, with 8 of these replicated (loci: BTNL2HLA-DRAHLA-DRB5HLA-DQA1HLA-DOB and TAP2). For ACPA-negative RA, no smoking–SNP pairs passed the threshold for significance.

    Conclusion: Our study presents extended gene variation patterns involved in gene–smoking interaction in ACPA-positive, but not ACPA-negative, RA. Notably, variants in HLA-DRB1 and those in additional genes within the MHC class II region, but not in any other gene regions, showed interaction with smoking.

  • 12.
    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.

  • 13.
    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.

  • 14.
    Ljung, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Clinical Epidemiology Section, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.
    Holmqvist, Marie
    Addressing the hardest endpoint2020In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 59, no 3, p. 462-463Article in journal (Other academic)
  • 15.
    Mousavizadeh, Rouhollah
    et al.
    Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McCormack, Robert G
    Department of Orthopedic Surgery, University of British Columbia, Vancouver, BC, Canada.
    Scott, Alex
    Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
    Dexamethasone decreases substance P expression in human tendon cells: an in vitro study2015In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 54, no 2, p. 318-323Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Glucocorticoid injections are used by rheumatologists to treat chronic tendinopathy. Surprisingly, the mechanisms by which corticosteroids induce pain relief in this condition have not been investigated. Previous studies have shown local substance P (SP) levels to be correlated with tendon pain and tissue pathology. The objective of this study was to determine whether SP production in human tenocytes is modulated by exposure to dexamethasone.

    METHODS: Human tendon fibroblasts were cultured in the presence or absence of dexamethasone (1-400 nM), an inhibitor of the glucocorticoid receptor, RU486, recombinant TGF-β (2.5 or 5.0 ng/ml) or an inhibitor of the TGF-β receptor (A83.01), recombinant human IL-1β and IL-6. Expression levels of the genes encoding for SP (TAC1) and its preferred receptor (NK1R), IL-1α, IL-1β and IL-6 were determined with quantitative PCR and protein levels of SP were examined by EIA and western blot.

    RESULTS: Exposure of human tendon cells to dexamethasone resulted in a time-dependent reduction of mRNA for SP in both hamstrings and Achilles tenocytes, whereas NK1R was unaffected. The reduction of SP mRNA was dependent on signalling through the glucocorticoid receptor. SP protein was substantially decreased by dexamethasone. Dexamethasone also prevented induction of SP by IL-1β and by cyclic mechanical loading.

    CONCLUSION: This study demonstrates that dexamethasone treatment of human tendon fibroblasts reduces the expression of SP through a glucocorticoid receptor-dependent pathway. Drugs interfering with SP signalling could be a future target in the treatment of tendinopathy.

  • 16. Pullerits, Rille
    et al.
    d'Elia, Helena Forsblad
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Tarkowski, Andrej
    Carlsten, Hans
    The decrease of soluble RAGE levels in rheumatoid arthritis patients following hormone replacement therapy is associated with increased bone mineral density and diminished bone/cartilage turnover: a randomized controlled trial.2009In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 48, no 7, p. 785-90Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of the study was to prospectively investigate the effects of HRT on serum soluble receptor for advanced glycation end product (sRAGE) levels in RA patients and to determine whether sRAGE production is related to bone/cartilage metabolism.

    METHODS: Eighty-eight post-menopausal RA patients were randomized to receive vitamin D3 and calcium supplementation with or without HRT (oestradiol plus noretisterone acetate). The levels of total sRAGE in sera were measured before, 1 and 2 years after treatment initiation. Potential associations between sRAGE levels, bone/cartilage metabolic markers and BMD were investigated.

    RESULTS: Patients receiving HRT displayed significantly decreased levels of serum sRAGE at 1 and 2 years as compared with levels at study entry. The increase in serum oestradiol was associated with the decline in sRAGE levels. Importantly, sRAGE levels at baseline significantly correlated with bone/cartilage turnover markers including C-terminal propeptide of type I procollagen, carboxyterminal telopeptide of type I collagen and cartilage oligomeric matrix protein, and the decrease of sRAGE levels paralleled with diminished concentration of these molecules. BMD in hip and femoral neck and progression of Larsen score at 1 year were associated with baseline sRAGE levels. The decline in sRAGE levels significantly correlated with an increase in total BMD following 2 years of treatment in patients receiving HRT but not in the control group.

    CONCLUSION: Our findings suggest that HRT decreases the levels of endogenous sRAGE in post-menopausal RA patients implicating its role in sRAGE regulation. In addition, serum sRAGE was associated with BMD and markers of bone/cartilage metabolism. These data suggest that sRAGE is involved directly or indirectly in bone metabolism. Trial registration. Current Controlled Trials, ISRCTN46523456, http://www.controlled-trials.com/isrctn/search.html?srch=ISRCTN46523456.

  • 17.
    Riazzoli, Jenny
    et al.
    Department of Medicine, Rheumatology Unit, Karolinska Institute, Karolinska University Hospital, Stockholm.
    Nilsson, Jan-Åke
    Department of Rheumatology, Malmö University Hospital, Malmö.
    Teleman, Annika
    Department of Rheumatology, Spenshult Hospital, Halmstad.
    Petersson, Ingemar F
    Departments of Orthopaedics and Rheumatology, Lund University Hospital, Lund .
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Jacobsson, Lennart T H
    Department of Rheumatology, Malmö University Hospital, Malmö.
    van Vollenhoven, Ronald F
    Department of Medicine, Rheumatology Unit, Karolinska Institute, Karolinska University Hospital, Stockholm.
    Patient-reported 28 swollen and tender joint counts accurately represent RA disease activity and can be used to assess therapy responses at the group level2010In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 49, no 11, p. 2098-2103Article in journal (Refereed)
    Abstract [en]

    Objective. Formal joint assessments are critically important to improve rheumatological care of patients with RA. The aim of this study was to determine the usefulness of patient-recorded 28 tender joint counts (TJCs) and swollen joint counts (SJCs) using a tablet personal computer and to explore the possibility of using patient-recorded data to calculate 28-joint DAS (DAS-28) and EULAR response.

    Methods. Forty-seven patients were included before initiation of adalimumab therapy and assessed at baseline and after 3 months. SJC and TJC were registered by the patients and thereafter by an experienced rheumatology specialist. Changes were correlated using Spearman’s rank correlation test.

    Results. The correlations between SJC and TJC derived by the physician and the patient at baseline were excellent (r = 0.78 and 0.87, respectively P < 0.01 for both). After 3 months, the correlations were less strong (0.645 and 0.745, respectively, P < 0.001 for both). When using the patient-derived SJC/TJC for calculation of the DAS-28 (patDAS-28), similar values were obtained, and correlations between DAS-28 and patDAS-28 were excellent (r = 0.91 at baseline, r = 0.90 at 3 months). According to the EULAR response criteria, the percentage of responders at the group level was nearly identical, although there was some disagreement at the individual level when DAS-28 and patDAS-28 were used to determine response to therapy.

    Conclusion. Patient-reported SJC and TJC can in research settings be used instead of physician-reported ones. Patient-derived SJC and TJC may also make it possible for rheumatologists to obtain quantitative joint count recordings much more frequently than is feasible for traditional joint counts.

  • 18. Simard, Julia F
    et al.
    Arkema, Elizabeth V
    Sundström, Anders
    Geborek, Pierre
    Saxne, Tore
    Baecklund, Eva
    Coster, Lars
    Dackhammar, Christina
    Jacobsson, Lennart
    Feltelius, Nils
    Lindblad, Staffan
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Klareskog, Lars
    van Vollenhoven, Ronald F
    Neovius, Martin
    Askling, Johan
    Ten years with biologics: to whom do data on effectiveness and safety apply?2011In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 50, no 1, p. 204-213Article in journal (Refereed)
    Abstract [en]

    The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.

  • 19.
    Sundström, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. University Hospital, Umeå.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Interaction between dietary sodium and smoking increases the risk for rheumatoid arthritis: results from a nested case-control study2015In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 54, no 3, p. 487-493Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Recent studies in animal models and on human cells have shown an effect of sodium chloride (NaCl) on Th17 cells promoting inflammation. The aim of this study was to evaluate the impact of NaCl intake on the risk of development of RA.

    METHODS: A nested case-control study was performed using population-based prospective data from the Västerbotten Intervention Programme. The study included 386 individuals who had stated their dietary habits as part of a community intervention programme a median of 7.7 years before the onset of symptoms of RA. For comparison, 1886 matched controls were identified from the same database and co-analysed.

    RESULTS: No significant association was found between sodium intake and the development of RA when all of the individuals were included. In analyses stratified for smoking status at the time of the examination, sodium intake more than doubled the risk for RA among smokers [odds ratio (OR) 2.26 (95% CI 1.06, 4.81)]. This was not observed among non-smokers. Additive interaction analysis of smoking and cases with the highest tertile of sodium intake revealed that 54% of the increased risk of developing RA from these exposures was due to interaction between them [attributable proportion 0.54 (95% CI 0.26, 0.82)]. The risk was further increased for the development of anti-CCP-positive and/or HLA shared epitope-positive RA.

    CONCLUSION: Although we were unable to confirm our stated hypothesis, our results that high sodium consumption among smokers was associated with the risk of RA may provide new insights into the impact of smoking in RA development.

  • 20. van Delft, Myrthe A. M.
    et al.
    Verheul, Marije K.
    Burgers, Leonie E.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    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 switching2018In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 57, no 9, p. 1583-1591Article in journal (Refereed)
    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.

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