Publications by authors named "Provan S"

66 Publications

Calcium supplementation and inflammation increase mortality in rheumatoid arthritis: A 15-year cohort study in 609 patients from the Oslo Rheumatoid Arthritis Register.

Semin Arthritis Rheum 2017 02 26;46(4):411-417. Epub 2016 Jul 26.

Department of Rheumatology, Diakonhjemmet Hospital, Pb23 Vinderen, N-0319 Oslo, Norway.

Objective: To investigate whether osteoporosis or use of calcium supplementations predict all-cause mortality, or death from CVD, in a longitudinal cohort of patients with rheumatoid arthritis (RA).

Methods: Patients in the Oslo RA register (ORAR) were examined, and bone mineral density was measured in 1996. The cohort was linked to the Norwegian Cause of Death registry on December 31, 2010. Death from CVD was defined in 3 following different outcomes: (1) primary atherosclerotic death, (2) atherosclerotic death as one of the 5 listed causes of death, and (3) CVD according to World Health Organization (WHO) definition as primary cause of death. Baseline predictors of all-cause mortality and death from CVD were identified in separate Cox regression models, using backwards selection. Sensitivity analyses were performed including analyses of interactions and competing risk.

Results: A total of 609 patients were examined in 1996/1997. By December 31, 2010, 162 patients (27%) had died, resulting in 7439 observed patient-years. Of the deceased, 40 (24.7%) had primary atherosclerotic death. In the final model of all-cause mortality increased baseline ESR [hazard ratio (HR) 1.02 per mm/h, 95% CI: 1.01-1.03], calcium supplementation (1.74, 1.07-2.84), and osteoporosis, defined as a T score ≤2.5 SD at any location, (1.58, 1.07-2.32) predicted higher mortality rates, in models adjusted for age, gender, and a propensity score. In the final model of primary atherosclerotic death, increased ESR (1.03 per mm/h, 1.01-1.05) and calcium supplementation (3.39, 1.41-8.08), predicted higher mortality.

Conclusions: Increased baseline ESR and use of calcium supplementation were predictors of increased all-cause mortality and risk of death from CVD in this longitudinal study of patients with RA.
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http://dx.doi.org/10.1016/j.semarthrit.2016.07.011DOI Listing
February 2017

Predictive Value of Arterial Stiffness and Subclinical Carotid Atherosclerosis for Cardiovascular Disease in Patients with Rheumatoid Arthritis.

J Rheumatol 2016 09 15;43(9):1622-30. Epub 2016 Jun 15.

From the Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital; Section of Vascular Investigations, Oslo University Hospital Aker; National Resource Centre for Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital, Oslo; Martina Hansens Hospital, Bærum; Division of Rheumatology, Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.E. Ikdahl, MD, Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital; S. Rollefstad, MD, PhD, Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital; G. Wibetoe, MD, Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital; I.C. Olsen, PhD, Department of Rheumatology, Diakonhjemmet Hospital; I.J. Berg, MD, Department of Rheumatology, Diakonhjemmet Hospital; J. Hisdal, DrPhilos, Section of Vascular Investigations, Oslo University Hospital Aker; T. Uhlig, MD, Professor, National Resource Centre for Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital; G. Haugeberg, MD, Professor, Martina Hansens Hospital, and Division of Rheumatology, Department of Neuroscience, Norwegian University of Science and Technology; T.K. Kvien, MD, Professor, Department of Rheumatology, Diakonhjemmet Hospital; S.A. Provan, MD, PhD, Department of Rheumatology, Diakonhjemmet Hospital; A.G. Semb, MD, PhD, Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital.

Objective: We evaluated the predictive value of these vascular biomarkers for cardiovascular disease (CVD) events in patients with rheumatoid arthritis (RA): aortic pulse wave velocity (aPWV), augmentation index (AIx), carotid intima-media thickness (cIMT), and carotid plaques (CP). They are often used as risk markers for CVD.

Methods: In 2007, 138 patients with RA underwent clinical examination, laboratory tests, blood pressure testing, and vascular biomarker measurements. Occurrence of CVD events was recorded in 2013. Predictive values were assessed in Kaplan-Meier plots, log-rank, and crude and adjusted Cox proportional hazard (PH) regression analyses.

Results: Baseline median age and disease duration was 59.0 years and 17.0 years, respectively, and 76.1% were women. CVD events occurred in 10 patients (7.2%) during a mean followup of 5.4 years. Compared with patients with low aPWV, AIx, cIMT, and without CP, patients with high aPWV (p < 0.001), high AIx (p = 0.04), high cIMT (p = 0.01), and CP (p < 0.005) at baseline experienced more CVD events. In crude Cox PH regression analyses, aPWV (p < 0.001), cIMT (p < 0.001), age (p = 0.01), statin (p = 0.01), and corticosteroid use (p = 0.01) were predictive of CVD events, while AIx was nonsignificant (p = 0.19). The Cox PH regression estimates for vascular biomarkers were not significantly altered when adjusting individually for demographic variables, traditional CVD risk factors, RA disease-related variables, or medication. All patients who developed CVD had CP at baseline.

Conclusion: CP, aPWV, and cIMT were predictive of CVD events in this cohort of patients with RA. Future studies are warranted to examine the additive value of arterial stiffness and carotid atherosclerosis markers in CVD risk algorithms. Regional Ethical Committee approval numbers 2009/1582 and 2009/1583.
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http://dx.doi.org/10.3899/jrheum.160053DOI Listing
September 2016

The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab, Abatacept and Tociliziumab.

PLoS One 2015 26;10(6):e0130709. Epub 2015 Jun 26.

Preventive Cardio-Rheuma clinic, Dept. of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objectives: To assess whether treatment with one of three novel biological DMARDs; rituximab, abatacept or tocilizumab reduce cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA).

Methods: This is an open, observational and prospective study with visits at baseline, 3, 6, and 12 months. Patients were assigned to receive rituximab, abatacept or tocilizumab according to clinical indications assessed by an independent rheumatologist. Disease activity was quantified by the disease activity score (DAS28) and extensive ultrasonography. CVD risk was assessed by total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), blood pressure and arterial stiffness measurements [pulse wave velocity (PWV) and augmentation index (AIx)]. Within group change in disease activity and CVD risk over 3 months was explored using paired samples bivariate tests. Predictors of change in CVD risk at 3 months were identified in linear regression models. Changes in CVD risk markers over the 12- month follow-up in patients receiving rituximab were assessed by mixed models repeated analyses.

Results: 24 patients on rituximab, 5 on abatacept and 7 on tocilizumab were included. At 3 months PWV was significantly reduced in the tocilizumab group only, but at 12 months rituximab patients showed a significant reduction in PWV. Reduced inflammation at 3 months was associated with increased TC and HDL-c in the entire cohort.

Conclusion: Treatment with tocilizumab and rituximab reduces PWV, a marker of CVD risk, in patients with RA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130709PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482693PMC
April 2016

CRP and ASDAS are associated with future elevated arterial stiffness, a risk marker of cardiovascular disease, in patients with ankylosing spondylitis: results after 5-year follow-up.

Ann Rheum Dis 2015 Aug 20;74(8):1562-6. Epub 2015 Mar 20.

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objective: To identify factors associated with elevated arterial stiffness in a 5-year follow-up of patients with ankylosing spondylitis (AS).

Methods: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath AS disease activity index (BASDAI) and AS disease activity score (ASDAS) were recorded in 2003, and arterial stiffness (Augmentation Index (AIx) and pulse wave velocity (PWV)) in 2008/2009. Patients were grouped into quartiles according to baseline CRP, ESR and BASDAI and four ASDAS groups. Trend analyses were performed using ANCOVA (AIx/PWV as dependent variable) with separate models for CRP, ESR, BASDAI and ASDAS (age and gender adjusted). Independent predictors of future AIx and PWV levels were identified in multivariate linear regression models.

Results: In total, 85 patients participated. Increasing baseline values of CRP, ESR and ASDAS were associated with elevated AIx on follow-up (p(trend) 0.01, 0.05 and 0.04, respectively). Similar non-significant patterns were seen for PWV. In the multivariate analyses, baseline CRP and ASDAS were independently associated with future elevated AIx (p=0.03 and0.02, respectively). In the multivariate PWV model, results for CRP and ASDAS were non-significant.

Conclusions: Baseline CRP and ASDAS were associated with future elevated arterial stiffness measured as AIx, supporting that disease activity is related to future risk of cardiovascular disease in patients with AS.
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http://dx.doi.org/10.1136/annrheumdis-2014-206773DOI Listing
August 2015

Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study.

Scand J Rheumatol 2015 ;44(2):118-24

National Advisory Unit on Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital , Oslo , Norway.

Objectives: Insight into the most important inflammatory pathways in ankylosing spondylitis (AS) could be of importance in risk stratification and the development of treatment strategies. Therefore, we aimed to compare circulating levels of inflammatory biomarkers between AS patients and controls, and explore associations between these biomarkers and clinical measures of disease activity.

Method: In a cross-sectional study, 143 AS patients were compared with 124 population controls. Blood samples were analysed by immunoassays for interleukin (IL)-6, IL-17a, IL-23, soluble tumour necrosis factor receptor 1 (sTNF-R1) and 2 (sTNF-R2), and osteoprotegerin (OPG). Disease activity was measured by the AS Disease Activity Score (ASDAS) and the Bath AS Disease Activity Index (BASDAI).

Results: Analysis of covariance (ANCOVA) demonstrated elevated plasma levels of sTNF-R1 [geometrical mean 0.94 (95% CI 0.88-1.00) vs. 0.83 (95% CI 0.78-0.89) ng/mL, p < 0.01] and OPG (2.3, 95% CI 2.1-2.4 vs. 2.0, 95% CI 1.9-2.2 ng/mL, p = 0.02) and, although not significant, of IL-23 (122, 95% CI 108-139 vs. 106, 95% CI 93-120 pg/mL, p = 0.07) in AS patients vs.

Controls: More AS patients had a high level of sTNF-R2 than controls (22 vs. 1, p < 0.01). No differences between the groups were seen for IL-6 and IL-17a. In patients, no significant associations were seen between inflammatory markers and disease activity measures after adjusting for personal characteristics.

Conclusion: Significantly higher plasma levels of sTNF-R1, sTNF-R2, and OPG and numerically but non-significantly higher levels of IL-23 were found in AS patients compared to controls, indicating that these cytokines and cytokine receptors are important inflammatory pathways. Clinical measures of disease activity were not significantly correlated with circulating inflammatory markers.
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http://dx.doi.org/10.3109/03009742.2014.956142DOI Listing
May 2015

Disease activity in ankylosing spondylitis and associations to markers of vascular pathology and traditional cardiovascular disease risk factors: a cross-sectional study.

J Rheumatol 2015 Apr 1;42(4):645-53. Epub 2015 Feb 1.

From the Department of Rheumatology, Diakonhjemmet Hospital, and Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital Ullevål, and University of Oslo, Oslo, Norway; Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.I.J. Berg, MD; H. Dagfinrud, PhD; I.C. Olsen, PhD; T.K. Kvien, MD, PhD; A.G. Semb, MD, PhD; S.A. Provan, MD, PhD, Department of Rheumatology, Diakonhjemmet Hospital; D. van der Heijde, MD, PhD, Department of Rheumatology, Diakonhjemmet Hospital and Department of Rheumatology, Leiden University Medical Center; I. Seljeflot, PhD, Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital Ullevål, and Faculty of Medicine, University of Oslo.

Objective: To compare the risk of cardiovascular disease (CVD) in ankylosing spondylitis (AS) and population controls, and to examine the associations between disease activity and CVD risk.

Methods: A cross-sectional study was done of patients with AS grouped according to Ankylosing Spondylitis Disease Activity Score (ASDAS) into ASDAS-high and ASDAS-low. Markers of vascular pathology, impaired endothelial function [asymmetric dimethylarginine (ADMA)], and arterial stiffness [augmentation index (AIx) and pulse wave velocity (PWV)], and traditional CVD risk factors [blood pressure, lipids, body mass index (BMI), CVD risk scores] were compared between AS and controls as well as across ASDAS-high versus ASDAS-low versus controls using ANCOVA analyses.

Results: Altogether, 151 patients with AS and 134 controls participated. Patients had elevated ADMA (µmol/l) and AIx (%) compared to controls: mean difference (95% CI): 0.05 (0.03, 0.07), p < 0.001 and 2.6 (0.8, 4.3), p = 0.01, respectively. AIx increased with higher ASDAS level, p(trend) < 0.04. There were no significant group differences of PWV. BMI was higher in ASDAS-high compared to ASDAS-low (p = 0.02). Total cholesterol was lower in AS compared to controls, and lower with higher ASDAS, p(trend) = 0.02. CVD risk scores were similar across groups except for Reynolds Risk Score, where the ASDAS-high group had a significantly higher score, compared to both ASDAS-low and controls.

Conclusion: Elevated ADMA and AIx in AS support a higher CVD risk in AS. Elevated AIx and BMI in AS with high ASDAS indicate an association between disease activity and CVD risk. Lower total cholesterol in AS may contribute to underestimation of CVD risk.
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http://dx.doi.org/10.3899/jrheum.141018DOI Listing
April 2015

Efficacy of high intensity exercise on disease activity and cardiovascular risk in active axial spondyloarthritis: a randomized controlled pilot study.

PLoS One 2014 30;9(9):e108688. Epub 2014 Sep 30.

National Advisory Unit on Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway; Department of Health Sciences, University of Oslo, Oslo, Norway.

Background: Physical therapy is recommended for the management of axial spondyloarthritis (axSpA) and flexibility exercises have traditionally been the main focus. Cardiovascular (CV) diseases are considered as a major health concern in axSpA and there is strong evidence that endurance and strength exercise protects against CV diseases. Therefore, the aim of this study was to investigate the efficacy of high intensity endurance and strength exercise on disease activity and CV health in patients with active axSpA.

Methods: In a single blinded randomized controlled pilot study the exercise group (EG) performed 12 weeks of endurance and strength exercise while the control group (CG) received treatment as usual. The primary outcome was the Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS). Secondary outcomes included patient reported disease activity (Bath AS Disease Activity Index [BASDAI]), physical function (Bath AS Functional Index [BASFI]), and CV risk factors measured by arterial stiffness (Augmentation Index [Alx]) and Pulse Wave Velocity [PWV]), cardiorespiratory fitness (VO2 peak) and body composition. ANCOVA on the post intervention values with baseline values as covariates was used to assess group differences, and Mann Whitney U-test was used for outcomes with skewed residuals.

Results: Twenty-eight patients were included and 24 (EG, n = 10, CG, n = 14) completed the study. A mean treatment effect of -0.7 (95%CI: -1.4, 0.1) was seen in ASDAS score. Treatment effects were also observed in secondary outcomes (mean group difference [95%CI]): BASDAI: -2.0 (-3.6, -0.4), BASFI: -1.4 (-2.6, -0.3), arterial stiffness (estimated median group differences [95% CI]): AIx (%): -5.3 (-11.0, -0.5), and for PVW (m/s): -0.3 (-0.7, 0.0), VO2 peak (ml/kg/min) (mean group difference [95%CI]: 3.7 (2.1, 5.2) and trunk fat (%): -1.8 (-3.0, -0.6). No adverse events occurred.

Conclusion: High intensity exercise improved disease activity and reduced CV risk factors in patients with active axSpA. These effects will be further explored in a larger trial.

Trial Registration: ClinicalTrials.gov NCT01436942.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108688PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182541PMC
June 2015

Relationship between types of radiographic damage and disability in patients with rheumatoid arthritis in the EURIDISS cohort: a longitudinal study.

Rheumatology (Oxford) 2015 Jan 26;54(1):83-90. Epub 2014 Jul 26.

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands, Department of Rheumatology, University Hospital La Paz, Madrid, Spain, Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology Center, University of Amsterdam, Amsterdam, Department of Rheumatology, Atrium Medical Center Heerlen, Heerlen, The Netherlands, Department of Rheumatology, Diakonhjemmet Hospital, National Unit on Rehabilitation in Rheumatology, National Advisory Unit on Rehabilitation in Rheumatology, Department of Epidemiology, Maastricht University, Maastricht, The Netherlands and Department of Rheumatology, Hospital Garcia de Orta, Almada, Portugal. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands, Department of Rheumatology, University Hospital La Paz, Madrid, Spain, Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology Center, University of Amsterdam, Amsterdam, Department of Rheumatology, Atrium Medical Center Heerlen, Heerlen, The Netherlands, Department of Rheumatology, Diakonhjemmet Hospital, National Unit on Rehabilitation in Rheumatology, National Advisory Unit on Rehabilitation in Rheumatology, Department of Epidemiology, Maastricht University, Maastricht, The Netherlands and Department of Rheumatology, Hospital Garcia de Orta, Almada, Portugal.

Objective: The aim of this study was to assess if any of the different types of radiographic damage [true joint space narrowing (JSN), (sub)luxation and erosions] are preferentially related to disability in patients with RA.

Methods: Longitudinal data from 167 RA patients from the European Research on Incapacitating Diseases and Social Support study over 10 years were analysed to investigate the relationship between the three types of radiographic damage and disability [grip strength, HAQ and the dexterity scale in the Arthritis Impact Measurement Scales (AIMS)]. A longitudinal analysis including separate models per type of damage and joint group and combined models including all information was conducted.

Results: All types of damage were inversely related to grip strength in the analysis of separate models, but only true JSN independently remained statistically significant in the combined analysis [β = -0.087 (95% CI -0.151, -0.022)]. Neither JSN, (sub)luxation nor erosions were associated with HAQ score, while erosions were associated with AIMS dexterity only in the analysis of separate models. After stratifying for hand joint group, erosions at MCP joints [β = -0.288 (95% CI -0.556, -0.019)] and true JSN at the wrist [β = -0.132 (95% CI -0.234, -0.030)] were significantly related to grip strength. Erosions at the PIP [β = 0.017 (95% CI 0.005, 0.028)] and MCP joints [β = 0.114 (95% CI 0.010, 0.217)] was the only type of damage associated with HAQ and AIMS dexterity, respectively.

Conclusion: All types of radiographically visible joint damage interfere with important aspects of physical functions. True JSN is most closely related to hand function.
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http://dx.doi.org/10.1093/rheumatology/keu284DOI Listing
January 2015

Uveitis is associated with hypertension and atherosclerosis in patients with ankylosing spondylitis: a cross-sectional study.

Semin Arthritis Rheum 2014 Dec 20;44(3):309-13. Epub 2014 May 20.

Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vinderen, Oslo N-0319, Norway.

Objectives: Uveitis is the most common extra-articular manifestation in patients with ankylosing spondylitis (AS), but the literature describing AS patients with a history of uveitis is limited. The objective was to examine if a history of uveitis in patients with AS is associated with increased disease activity and functional impairment and to investigate whether uveitis is associated with an increased frequency of cardiovascular comorbidities, defined here as hypertension and atherosclerosis.

Methods: Data were recorded cross-sectionally through patient interviews, blood samples, clinical examination, and questionnaires. Carotid plaques were identified by ultrasonography. AS disease activity and function were compared across categories of uveitis using ANCOVA analyses. Associations between uveitis and hypertension and atherosclerosis [atherosclerotic cardiovascular disease (CVD) and/or carotid plaque] were analyzed in multivariate logistic regression models.

Results: Of 159 patients with AS (61.6% male, mean age 50.5 years), 84 (52.8%) had experienced one or more episodes of uveitis. AS disease activity was higher in patients with a history of uveitis, statistically significant for functional impairment [Bath AS Functional Index (BASFI)] [mean difference (95% CI)] lnBASFI = 0.2 (0.0-0.3), p = 0.05. Patients with uveitis had an increased odds ratio [OR (95% CI)] for hypertension [3.29 (1.29-8.41), p = 0.01] and atherosclerosis [2.57 (1.15-5.72), p = 0.02].

Conclusions: AS patients with a history of uveitis had non-significantly higher disease activity and significantly higher functional impairment. A history of uveitis was associated with hypertension as well as atherosclerosis. These results may be important in identifying AS patients with elevated risk of CVD but should be confirmed in longitudinal cohorts.
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http://dx.doi.org/10.1016/j.semarthrit.2014.05.017DOI Listing
December 2014

Hand, hip and knee osteoarthritis in a Norwegian population-based study--the MUST protocol.

BMC Musculoskelet Disord 2013 Jul 5;14:201. Epub 2013 Jul 5.

National Resource, Center for rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Background: Knowledge about the prevalence and consequences of osteoarthritis (OA) in the Norwegian population is limited. This study has been designed to gain a greater understanding of musculoskeletal pain in the general population with a focus on clinically and radiologically confirmed OA, as well as risk factors, consequences, and management of OA.

Methods/design: The Musculoskeletal pain in Ullensaker STudy (MUST) has been designed as an observational study comprising a population-based postal survey and a comprehensive clinical examination of a sub-sample with self-reported OA (MUST OA cohort). All inhabitants in Ullensaker municipality, Norway, aged 40 to 79 years receive the initial population-based postal survey questionnaire with questions about life style, general health, musculoskeletal pain, self-reported OA, comorbidities, health care utilisation, medication use, and functional ability. Participants who self-report OA in their hip, knee and/or hand joints are asked to attend a comprehensive clinical examination at Diakonhjemmet Hospital, Oslo, including a comprehensive medical examination, performance-based functional tests, different imaging modalities, cardiovascular assessment, blood and urine samples, and a number of patient-reported questionnaires including five OA disease specific instruments. Data will be merged with six national data registries. A subsample of those who receive the questionnaire has previously participated in postal surveys conducted in 1990, 1994, and 2004 with data on musculoskeletal pain and functional ability in addition to demographic characteristics and a number of health related factors. This subsample constitutes a population based cohort with 20 years follow-up.

Discussion: This protocol describes the design of an observational population-based study that will involve the collection of data from a postal survey on musculoskeletal pain, and a comprehensive clinical examination on those with self-reported hand, hip and/or knee OA. These data, in addition to data from national registries, will provide unique insights into clinically and radiologically confirmed OA with respect to risk factors, consequences, and management.
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http://dx.doi.org/10.1186/1471-2474-14-201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704709PMC
July 2013

Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis.

PLoS One 2013 17;8(4):e60970. Epub 2013 Apr 17.

Department of Medical Genetics, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.

Objective: Apolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers.

Method: A Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs).

Results: In the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2 < ε3/ε3 < ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative.

Conclusion: APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060970PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629235PMC
November 2013

Carotid plaque characteristics and disease activity in rheumatoid arthritis.

J Rheumatol 2013 Apr 15;40(4):359-68. Epub 2013 Jan 15.

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objective: Carotid plaques (CP) are predictive of acute coronary syndrome in patients with rheumatoid arthritis (RA), suggesting that atherosclerotic plaques in these patients are vulnerable. The objective of our study was to characterize vulnerability of CP in patients with RA compared to a control population, and between RA patients with different levels of disease activity.

Methods: Ultrasound examination of carotid arteries was performed in 152 patients with RA and 89 controls. CP echolucency was evaluated by the Gray-Scale Median (GSM) technique. Lower GSM values indicate higher vulnerability of plaques. CP characteristics were compared between RA patients with active disease and in remission, and between patients and controls. All analyses were performed with adjustment for confounding factors (sex, age, smoking, and blood pressure). Poisson regression analysis was used for count data, mixed modeling for GSM and area per plaque, and analysis of covariance for minimum GSM value per patient.

Results: Patients with RA more frequently had CP (median 2, range 0, 4) compared with controls (median 1, range 0, 3; p < 0.001), after adjustment for age and sex. Patients with active RA disease according to the Clinical Disease Activity Index (CDAI) had lower median GSM (p = 0.03), minimum GSM (p = 0.03), and a larger CP area (although the latter finding was not significant; p = 0.27), compared with patients with RA in remission. These findings were not confirmed for other disease measures (Simplified Disease Activity Index, Disease Activity Score-28, C-reactive protein, erythrocyte sedimentation rate).

Conclusion: Patients with RA had more CP compared with controls and patients in CDAI remission, and controls had more stable CP than patients with active disease; these findings point to the importance of achieving remission in RA.
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http://dx.doi.org/10.3899/jrheum.120621DOI Listing
April 2013

Cardiorespiratory fitness and cardiovascular risk in patients with ankylosing spondylitis: a cross-sectional comparative study.

Arthritis Care Res (Hoboken) 2013 Jun;65(6):969-76

University of Oslo and Diakonhjemmet Hospital, Oslo, Norway.

Objective: To investigate the associations between cardiorespiratory fitness (CRF) and the level of cardiovascular (CV) risk factors in patients with ankylosing spondylitis (AS) and controls.

Methods: In a cross-sectional comparative study, CRF was measured with a maximal treadmill test for estimation of peak oxygen uptake. Metabolic syndrome (MS), body composition, traditional CV risk factors, and inflammatory markers were assessed. Multivariable linear regression models were used to study the associations between CRF and CV risk factors. All models were adjusted for age, sex, and smoking, and for inflammation when C-reactive protein (CRP) level or erythrocyte sedimentation rate (ESR) were not already included as dependent variables.

Results: A total of 126 patients (mean ± SD age 47.9 ± 10.8 years) and 111 controls (mean ± SD age 52.1 ± 11.1 years) were included. There were significant inverse associations between CRF and body mass index, waist circumference, triglycerides, CRP level, and ESR (P < 0.001-0.03) for patients and controls. Also, significant associations were found between CRF and high-density lipoprotein (HDL) cholesterol (β = 0.03, P < 0.001) and blood pressure (BP; β = -0.9 for systolic and β = -0.6 for diastolic; P < 0.01) in controls, but these associations were not found in patients (β = 0, P = 0.69 for HDL cholesterol; β = -0.04, P = 0.87 for systolic pressure; and β = -0.14, P = 0.34 for diastolic pressure) (additional adjustments for medication). Higher CRF was associated with a lower risk for MS in both patients (odds ratio [OR] 0.91, P = 0.03) and controls (OR 0.89, P = 0.01).

Conclusion: CRF was associated with favorable levels of CV risk factors and lower risk of MS in both AS patients and controls. However, established findings of an association between CRF and BP and HDL cholesterol in healthy adults were not confirmed in AS patients.
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http://dx.doi.org/10.1002/acr.21926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619024PMC
June 2013

The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-α therapy in inflammatory arthropathies. Associations with aortic stiffness.

Atherosclerosis 2012 Nov 10;225(1):160-5. Epub 2012 Sep 10.

Department of Cardiology B, Oslo University Hospital Ullevaal, Pb 4956 Nydalen, 0424 Oslo, Norway.

Background: Anti-Tumor Necrosis Factor (TNF)-α therapy improves vascular pathology in inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The l-arginine/ADMA ratio is important for modulation of the nitric oxide synthase activity. We examined the effect of TNF-α antagonists on ADMA and l-arginine/ADMA, and associations between ADMA, L-arginine/ADMA, aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies.

Methods: Forty-eight patients who started with anti-TNF-α therapy were compared with a non-treated group of 32 patients. Plasma ADMA and L-arginine were assessed at baseline, 3 and 12 months. In a subgroup of 55 patients, aortic pulse wave velocity (aPWV) was measured at baseline, 3 and 12 moths, and CIMT was examined at baseline and 12 months.

Results: Anti-TNF-α therapy increased the L-arginine/ADMA ratio (mean [SD]) in the treatment group compared to the control group after 3 months (12 [29] vs. -13 [20], P < 0.001) and 12 months (7 [27] vs. -8 [19], P = 0.008), but did not affect ADMA (3 months: 0.00 [0.09] μmol/L vs. 0.02 [0.07] μmol/L, P = 0.42, 12 months: 0.01 [0.08] μmol/L vs. 0.01 [0.09] μmol/L, P = 0.88). Baseline aPWV was associated with ADMA (P = 0.02) and L-arginine/ADMA (P = 0.02) in multiple regression analyses, and the L-arginine/ADMA ratio was continuously associated with aPWV after initiation of anti-TNF-α therapy (P = 0.03). ADMA and L-arginine/ADMA were not correlated with CIMT.

Conclusion: Anti-TNF-α therapy improved the L-arginine/ADMA ratio in patients with inflammatory arthropathies. ADMA and the L-arginine/ADMA ratio were associated with aPWV, and might have a mechanistic role in the aortic stiffening observed in these patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.08.033DOI Listing
November 2012

Effect of 1-year anti-TNF-α therapy on aortic stiffness, carotid atherosclerosis, and calprotectin in inflammatory arthropathies: a controlled study.

Am J Hypertens 2012 Jun 1;25(6):644-50. Epub 2012 Mar 1.

Department of Cardiology B, Oslo University Hospital Ullevaal, Oslo, Norway.

Background: Premature arterial stiffening and atherosclerosis are increased in patients with inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The proinflammatory protein calprotectin is associated with inflammatory arthropathies, vascular pathology, and acute coronary events. We examined the long-term effects of treatment with tumor necrosis factor (TNF)-α antagonists on aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies, and the relationships to the levels of calprotectin.

Methods: Fifty-five patients with RA, AS, or PsA and a clinical indication for anti-TNF-α therapy were included and followed with regular examinations for 1 year. Thirty-six patients starting with anti-TNF-α therapy were compared with a nontreatment group of 19 patients. Examinations included assessments of aortic stiffness (aortic pulse wave velocity, aPWV), CIMT, and plasma calprotectin.

Results: After 1 year, aPWV (mean (s.d.)) was improved in the treatment group, but not in the control group (-0.54 [0.79] m/s vs. 0.06 [0.61] m/s, respectively; P = 0.004), and CIMT progression (median (quartile cut-points, 25th and 75th percentiles)) was reduced in the treatment group compared to the control group (-0.002 [-0.038, 0.030] mm vs. 0.030 [0.011, 0.043] mm, respectively; P = 0.01). In multivariable analyses, anti-TNF-α therapy over time was associated with improved aPWV (P = 0.02) and reduced CIMT progression (P = 0.04), and calprotectin was longitudinally associated with aPWV (P = 0.02).

Conclusions: Long-term anti-TNF-α therapy improved aortic stiffness and CIMT progression in patients with inflammatory arthropathies. Calprotectin may be a soluble biomarker reflecting aortic stiffening in these patients.
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http://dx.doi.org/10.1038/ajh.2012.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635528PMC
June 2012

Physical fitness in patients with ankylosing spondylitis: comparison with population controls.

Phys Ther 2012 Feb 17;92(2):298-309. Epub 2011 Nov 17.

Department of Health Sciences, University of Oslo, PO Box 1074, Blindern, Oslo 0316, Norway.

Background: Although flexibility traditionally has been the main focus for physical therapy in patients with ankylosing spondylitis (AS), there is now evidence for an increased risk of cardiovascular diseases (CVDs) in this group.

Objective: The purposes of this study were: (1) to compare physical fitness (cardiorespiratory fitness, muscular capacity, flexibility, and balance) in patients with AS and controls and (2) to explore associations between physical fitness and disease activity in the patient group.

Design: This was a cross-sectional study.

Methods: The physical fitness variables were cardiorespiratory fitness (treadmill test for estimation of peak oxygen uptake [V(O(2))peak]), muscular capacity (push-ups test), balance (30-second single-leg stand and walking in a figure-of-eight pattern), and flexibility (Bath Ankylosing Spondylitis Metrology Index [BASMI]). The Ankylosing Spondylitis Disease Activity Score (ASDAS) was used to assess disease activity. Group differences and associations were tested with the chi-square test for categorical variables, the Mann-Whitney U test for ordinal variables, and analysis of covariance for continuous variables.

Results: One hundred forty-nine of 250 of the invited patients with AS and 133 of 329 of the invited controls were included in the study. The mean ASDAS score of the patient group was 2.3 (range=0.5-4.7), and the median disease duration was 23 years (range=7-55). The patient group had significantly lower V(O(2)) peak values, with a mean difference of -2.7 mL·kg(-1)·min(-1) (95% confidence interval=-4.3, -1.1), and higher BASMI scores, with a mean difference of 1.6 (95% confidence interval=1.5, 1.8), compared with the control group. No group differences were found in balance or muscular capacity. In the patient group, significant inverse associations were found between ASDAS scores and V(O(2))peak and muscular capacity.

Limitations: The response rate was lower in the control group (40.4%) than in the patient group (59.6%).

Conclusion: The lower cardiorespiratory fitness and reduced flexibility in the AS group indicate that physical therapy programs should include cardiorespiratory fitness exercises as a basic component to reduce the risk of cardiovascular disease.
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http://dx.doi.org/10.2522/ptj.20110137DOI Listing
February 2012

The effects of whole body vibration on balance, joint position sense and cutaneous sensation.

Eur J Appl Physiol 2011 Dec 1;111(12):3069-77. Epub 2011 Apr 1.

Centre of Human and Aerospace Physiological Sciences, King's College London, 3.11 Shepherds House, Guys Campus, SE1 1UL London, UK.

Whole body vibration (WBV) may enhance muscular strength and power but little is known about its influence on sensory-motor function. Vibration of a single muscle or tendon affects the afferent system in a manner that depends on amplitude and frequency. WBV stimulates many muscle groups simultaneously and the frequencies and amplitudes used are different from many of the studies on single musculotendinous units. We investigated the effects of WBV at two amplitudes on balance, joint position sense (JPS) and cutaneous sensation in young healthy subjects. Eighteen adults (24.3 ± 1.5 years, 15 females) were assessed before WBV (five 1 min bouts, 30 Hz) then immediately, 15 and 30 min afterwards. Two amplitudes (4 and 8 mm peak to peak) were investigated on different occasions. Standing balance was assessed with feet together and eyes closed, and standing on one leg with eyes open and closed. JPS at the knee and ankle was assessed by repositioning tasks while cutaneous sensation was recorded from six sites in the lower limb using pressure aesthesiometry. Neither amplitude affected JPS (P > 0.05). There were minimal effects on balance only in the vertical plane and only 30 min after WBV (P < 0.05). Low amplitude vibration only reduced sensation at the foot and ankle immediately after WBV (P < 0.008). High amplitude vibration impaired sensation at the foot, ankle and posterior shank for the entire test period (P < 0.008). In young healthy individuals WBV did not affect JPS or static balance, but reduced cutaneous sensation. These data may have implications for older and clinical populations with compromised postural control.
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http://dx.doi.org/10.1007/s00421-011-1943-yDOI Listing
December 2011

Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study.

Ann Rheum Dis 2011 May 2;70(5):812-7. Epub 2011 Feb 2.

Department of Rheumatology, Diakonhjemmet Hospital, PB.23 Vindern, N-0319 Oslo,

Objectives: To compare markers of cardiovascular disease (CVD) risk between patients with rheumatoid arthritis (RA) in an active disease state and those with RA in remission, and to compare both groups with community controls.

Methods: 113 patients with RA and 86 community controls were assessed across a panel of biomarkers for CVD. RA in remission was defined as Clinical Disease Activity Index ≤2.8. Community controls were selected at random by Statistics Norway, and controls were matched with patients in the cohorts in strata using details of age, sex and residential area. A panel of biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP), total cholesterol, reactive hyperaemia index (RHI), pressure measurements, measures of arterial stiffness and intima-media thickness) were compared between patients with active RA and those with RA in remission. Both groups were compared with controls. In addition, biomarker levels were compared across subgroups based on anticyclic citrullinated peptide status, level of joint destruction and presence of extra-articular manifestations.

Results: Patients with active RA had significantly higher levels of NT-proBNP, brachial systolic pressure, augmentation index and central systolic pressure but lower cholesterol than patients in remission and controls. In addition, patients with active RA had significantly higher levels of pulse wave velocity and worse RHI than patients in remission. Comparison across other subgroups gave less consistent differentiations in levels of CVD risk markers.

Conclusion: Patients with active RA, but not those in remission, had significantly increased levels of CVD risk markers. These results link inflammatory activity to markers of CVD risk in patients with RA and may indirectly support the notion that remission in RA confers diminished cardiovascular morbidity.
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http://dx.doi.org/10.1136/ard.2010.141523DOI Listing
May 2011

Early prediction of increased arterial stiffness in patients with chronic inflammation: a 15-year followup study of 108 patients with rheumatoid arthritis.

J Rheumatol 2011 Apr 15;38(4):606-12. Epub 2011 Jan 15.

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objective: Patients with rheumatoid arthritis (RA), a chronic inflammatory disease, have increased cardiovascular morbidity and mortality. We investigated whether early markers of RA inflammatory disease activity could predict later increased levels of pulse-wave velocity (PWV) and augmentation index (AIx), 2 measures of arterial stiffness.

Methods: In total 238 patients with early RA were followed longitudinally and 108 were available for the 15-year followup examination. Comprehensive baseline clinical and radiographic data were collected in 1992. Arterial stiffness, measured as AIx and PWV (Sphygmocor apparatus), was recorded at the 15-year followup. Adjusted logistic univariate and multivariate analyses were performed with levels of AIx and PWV as the dependent variables, and variables reflecting baseline RA disease activity as possible predictors. The validity of the final models was examined in linear regression analyses.

Results: Baseline C-reactive protein (CRP) above the median predicted increased AIx (OR 3.52, 95% CI 1.04-11.90) and PWV (OR 4.84, 95% CI 1.39-16.83) at the 15-year assessment in multivariate models. Patients with elevated baseline CRP had significantly higher AIx (ß = 2.67, 95% CI 0.06-5.31, p = 0.045) and lnPWV (ß = 0.08, 95% CI 0.01-0.14, p = 0.02) after 15 years, after adjustments for age, sex, heart rate (AIx only) and mean arterial pressure.

Conclusion: Inflammation early in the RA disease course was associated with increased AIx and PWV after 15 years. These findings support the importance of early control of the inflammatory process in patients with RA.
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http://dx.doi.org/10.3899/jrheum.100689DOI Listing
April 2011

Changes in arterial stiffness during continued infliximab treatment in patients with inflammatory arthropathies.

Fundam Clin Pharmacol 2011 Aug 6;25(4):511-7. Epub 2010 Sep 6.

Division of Cardiology, Oslo University Hospital Aker, 0514 Oslo, Norway.

Chronic inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are associated with an increased risk of cardiovascular disease. TNF-α antagonists may improve vascular function in these patients and thus be beneficial with regard to cardiovascular disease. This study evaluated arterial stiffness and disease activity between two infusions with a TNF-α antagonist (infliximab) in patients with inflammatory arthropathies on long-term infliximab therapy. Augmentation index (AIx), aortic pulse wave velocity (aPWV), and disease activity were measured in 17 patients with RA, AS, or PsA who had been treated with infliximab for at least 12 months. The patients were examined immediately before their infliximab infusion and thereafter every 10th day until their next infusion scheduled at week 4-8. AIx and aPWV did not change during the period between two infliximab infusions. The patients had a temporary improvement in the general disease activity assessed on visual analogue scales by the patients (P = 0.04) and the investigator (P = 0.02) after the infusion. In the group of patients with RA, the Disease Activity Score (DAS28) changed significantly in a similar manner (P = 0.003). C-reactive protein and erythrocyte sedimentation rate remained unchanged. Infliximab infusions did not alter aortic pulse wave velocity or augmentation index in patients with inflammatory arthropathies who were on long-term infliximab therapy. Reductions in the general disease activity and DAS28 were not reflected in alterations of aortic stiffness or augmentation index.
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http://dx.doi.org/10.1111/j.1472-8206.2010.00872.xDOI Listing
August 2011

NT-proBNP predicts mortality in patients with rheumatoid arthritis: results from 10-year follow-up of the EURIDISS study.

Ann Rheum Dis 2010 Nov 4;69(11):1946-50. Epub 2010 Jun 4.

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objectives: Patients with rheumatoid arthritis (RA) have a higher mortality than the general population, and this increased mortality is related to demographic and disease variables. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor of mortality both in general and patient populations, but has not been shown to predict mortality in patients with RA. This study examines whether NT-proBNP can further improve the prediction of mortality in RA.

Methods: 182 patients with RA of 5-9 years disease duration were comprehensively examined in 1997. Serum samples were frozen and later batch analysed for NT-proBNP levels and other biomarkers. Adjusted univariate and logistic regression analyses were performed with death within the 10-year follow-up period as the dependent variable. Significant predictors were also examined as dichotomised variables.

Results: Mortality was predicted in univariate analyses by the following variables: age, sex, homozygosity for HLA-DRB1 shared epitope alleles, Health Assessment Questionnaire, 28-joint Disease Activity Score (DAS28) and NT-proBNP. A multivariate model with age, sex, DAS28 and NT-proBNP as independent variables showed the greatest discrimination.

Conclusion: NT-proBNP provided incremental information in the prediction of mortality in this cohort of patients with RA.
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http://dx.doi.org/10.1136/ard.2009.127704DOI Listing
November 2010

Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study.

Hypertension 2010 Feb 28;55(2):333-8. Epub 2009 Dec 28.

Department of Cardiology, Oslo University Hospital Aker, 0514 Oslo, Norway.

The chronic inflammatory state of rheumatoid arthritis and other inflammatory arthropathies, such as ankylosing spondylitis and psoriatic arthritis, contributes to the accelerated atherosclerosis associated with these conditions. This study evaluates the effect of treatment with tumor necrosis factor (TNF)-alpha antagonists on arterial stiffness in patients with inflammatory arthropathies. A total of 60 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and clinical indication for anti-TNF-alpha therapy were included. Thirty-five patients started with anti-TNF-alpha therapy and were compared with a nontreatment group of 25 patients. Aortic stiffness (aortic pulse wave velocity), augmentation index, and disease activity were assessed at baseline and after 3 months. Aortic pulse wave velocity (mean+/-SD) was reduced in the treatment group but not in the control group (-0.50+/-0.78 m/s versus 0.05+/-0.54 m/s, respectively; P=0.002). Concomitantly, C-reactive protein and the disease activity score were reduced in the treatment group (-9.3+/-20.2 mg/L [P<0.001] and -0.74+/-0.91 [P=0.004]). Augmentation index remained unchanged in both groups (0.1+/-7.1% versus -1.0+/-5.8%, respectively; P=0.53). In a multivariate linear regression model, only treatment with TNF-alpha antagonist and change in mean arterial pressure predicted alterations in aortic pulse wave velocity. In summary, anti-TNF-alpha therapy improved aortic stiffness in patients with inflammatory arthropathies. These findings support the idea that anti-inflammatory treatment has a favorable effect on cardiovascular risk in patients with inflammatory arthropathies.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.143982DOI Listing
February 2010

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.

Ann Rheum Dis 2010 Feb 22;69(2):325-31. Epub 2009 Sep 22.

Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands.

Objectives: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA).

Methods: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis.

Results: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk.

Conclusions: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.
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http://dx.doi.org/10.1136/ard.2009.113696DOI Listing
February 2010

Effect of high-intensity statin treatment in rheumatoid arthritis: a case with possible coronary atheroma regression and progression of rheumatoid valve degeneration.

BMJ Case Rep 2009 21;2009. Epub 2009 Jun 21.

Diakonhjemmet Hospital, Rheumatology, PO Box 23 Vinderen, Oslo, NO-0319, Norway.

Rheumatoid arthritis (RA) is complicated by high mortality from cardiovascular disease. Statins have been shown to reduce cardiovascular disease events by approximately 30% and to induce coronary atheroma regression. There is no such documentation in patients with RA. This report describes a 49-year-old patient with RA who developed coronary atherosclerosis and rheumatoid valve disease. She underwent coronary artery bypass graft operation with two bypasses and a biological aortic valve replacement. Simultaneously, she was started on atorvastatin 80 mg, and low-density lipoprotein cholesterol reached 1.79 mmol/l and high-density lipoprotein cholesterol reached 1.59 mmol/l. One year after the heart surgery, she developed rheumatoid disease of the mitral valve. Coronary angiography revealed no signs of filling defect in her native coronary arteries. This case indicates that high-dose statin treatment may induce coronary atheroma regression in RA patients and that the rheumatoid valve disease process is not modulated by statins.
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http://dx.doi.org/10.1136/bcr.08.2008.0717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029050PMC
July 2011

The association between disease activity and NT-proBNP in 238 patients with rheumatoid arthritis: a 10-year longitudinal study.

Arthritis Res Ther 2008 23;10(3):R70. Epub 2008 Jun 23.

Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vindern, N-0319 Oslo, Norway.

Introduction: Disease activity in patients with rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, of which N-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor. Our objective was to examine the cross-sectional and longitudinal associations between markers of inflammation, measures of RA disease activity, medication used in the treatment of RA, and NT-proBNP levels (dependent variable).

Methods: Two hundred thirty-eight patients with RA of less than 4 years in duration were followed longitudinally with three comprehensive assessments of clinical and radiographic data over a 10-year period. Serum samples were frozen and later batch-analyzed for NT-proBNP levels and other biomarkers. Bivariate, multivariate, and repeated analyses were performed.

Results: C-reactive protein (CRP) levels at baseline were cross-sectionally associated with NT-proBNP levels after adjustment for age and gender (r2 adjusted = 0.23; P < 0.05). At the 10-year follow-up, risk factors for cardiovascular disease were recorded. Duration of RA and CRP levels were independently associated with NT-proBNP in the final model that was adjusted for gender, age, and creatinine levels (r2 adjusted = 0.38; P < 0.001). In the longitudinal analyses, which adjusted for age, gender, and time of follow-up, we found that repeated measures of CRP predicted NT-proBNP levels (P < 0.001).

Conclusion: CRP levels are linearly associated with levels of NT-proBNP in cross-sectional and longitudinal analyses of patients with RA. The independent associations of NT-proBNP levels and markers of disease activity with clinical cardiovascular endpoints need to be further investigated.
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http://dx.doi.org/10.1186/ar2442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483462PMC
December 2008

[The many faces of endocarditis].

Tidsskr Nor Laegeforen 2004 Jul;124(13-14):1788-90

Medisinsk avdeling, Lovisenberg Diakonale Sykehus, 0456 Oslo.

Background: Over the past years we have had a relatively large number of patients in our hospital with endocarditis. There has been a variety of clinical presentations, as illustrated by the following case presentations.

Material And Methods: We have conducted a search in our data-based archives of the period from 1.1.1994 to 31.12.2001 and found 25 patients discharged with a diagnosis of endocarditis. We have chosen five case histories that we discuss in the context of published literature.

Results And Interpretation: The signs and symptoms presented include a stroke, severe back pain, a swollen knee, pneumonia and cardiac failure. We especially discuss intravenous drug users and endocarditis of the heart's right side.
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July 2004

Real-time detection of mitochondrial inhibition at frog motor nerve terminals using increases in the spatial variance in probability of transmitter release.

Neurosci Lett 1995 Feb;185(3):187-90

Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614-0577, USA.

The effects of Hg2+, methyl mercury, and flufenamic acid, all of which inhibit mitochondria, were examined at frog motor nerve terminals. Unbiased estimates of m (no. of transmitter quanta released), n (no. of functional release sites), p (probability of release), and vars p (spatial variance in p) were obtained using K(+)-induced asynchronous neurosecretion (m, n and p not having the same definitions as with nerve-evoked release). Transient but significant increases in m, n, p and vars p were found with all three agents. These findings indicate that mitochondrial inhibition and release of sequestered Ca2+ can be detected as a real-time increase in vars p. The results also suggest that changes in vars p might be used to differentiate between cellular (membrane) and subcellular (organellar) actions of drugs at the nerve terminal.
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http://dx.doi.org/10.1016/0304-3940(95)91365-oDOI Listing
February 1995

Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction.

Br J Pharmacol 1994 Apr;111(4):1103-10

Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614-0577.

1. The subcellular mechanism and site of action of linopirdine or DuP 996 (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) was investigated at the frog neuromuscular junction, using miniature endplate potential (m.e.p.p.) counts and a new method for obtaining unbiased estimates of n (number of functional release sites), p (probability of release), and varsp (spatial variance in p). 2. DuP 996 produced an increase in m (no. of quanta released), which was due to an increase in n and p. The increase in m was concentration-dependent over a range of 0.1-100 microM and completely reversible with 15 min of wash. There was a saturation in the increase in p, but not in the increase in m and n, for [DuP 996] > 10 microM. By contrast, there was no major change in varsp. 3. Block of presynaptic Na(+)- and Ca(2+)-channels with 3 microM tetrodoxin and 1.8 mM Co2+ prevented the m.e.p.p. frequency increase to DuP996, and this effect was completely reversed by washing. 4. Application of the neuronal Ca(2+)-channel blocker, omega-conotoxin GVIA (1 microM) brought about a rapid and profound decrease in the m.e.p.p. frequency increased produced by DuP996. The effect of the toxin was not reversed by prolonged washing. 5. Block of voltage-gated K(+)-channels with 100 microM 4-aminopyridine (4-AP) resulted in only a small (28%) increase in m. The combination of 4-AP (100 microM) and DuP996 (10 microM) produced an increase in m (189%) which was much greater than the sum of the responses to each agent alone. This increase in m was due solely to an increase in n, as p and varsp were unchanged.6. For [DuP 996] up to 100 gM, there was no apparent change in the mean size, amplitude distribution,or time course of m.e.p.ps, signifying that it had no anticholinesterase activity.7. It is concluded that DuP 996 increases the release of quantal transmitter but not the postsynaptic response to the quanta. This appears to involve an effect at the nerve terminal membrane, most likely an increase in Ca2+-conductance, and not an action to block K+-conductance or to release Ca2+ from intraterminal organelles.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1910115PMC
http://dx.doi.org/10.1111/j.1476-5381.1994.tb14858.xDOI Listing
April 1994

Unbiased estimates of quantal release parameters and spatial variation in the probability of neurosecretion.

Am J Physiol 1993 Apr;264(4 Pt 1):C1051-60

Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614-0577.

A procedure was developed for dealing with two problems that have impeded the use of quantal parameters in studies of transmitter release. The first, involving temporal and spatial biasing in the estimates for the number of functional release sites (n) and probability of release (p), was addressed by reducing temporal variance experimentally and calculating the bias produced by spatial variance in p (var(s)p). The second, involving inaccuracies in the use of nerve-evoked endplate potentials (EPPs), was circumvented by using only miniature EPPs (MEPPs). Intracellular recordings were made from isolated frog cutaneous pectoris, after decapitation and pithing of the animals, and the concentration of K+ ([K+]) was raised to 10 mM to increase the level of transmitter release. The number of quanta released (m) by the EPP was replaced by the number of MEPPs in a fixed time interval (bin), and 500 sequential bins used for each quantal estimate. With the use of 50-ms bins, estimates for var(s)p were consistently negative. This was due to too large a bin (and introduction of undetected temporal variance) because the use of smaller bins (5 ms) produced positive estimates of var(s)p. Increases in m, n, and p but not var(s)p were found in response to increases in [K+] or [Ca2+]/[Co2+]. La3+ (20 microM) produced increases in m and n, which peaked after 20 min and declined toward zero. There were also large increases in p and var(s)p, which peaked and declined only to initial control values. The increase in var(s)p was presumed to reflect La(3+)-induced release of Ca2+ from intracellular organelles. The results suggest that this approach may be used to obtain unbiased estimates of n and p and that the estimates of var(s)p may be useful for studying Ca2+ release from intraterminal organelles.
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http://dx.doi.org/10.1152/ajpcell.1993.264.4.C1051DOI Listing
April 1993

Aluminum inhibits glutamate release from transverse rat hippocampal slices: role of G proteins, Ca channels and protein kinase C.

Neurotoxicology 1992 ;13(2):413-20

College of Pharmacy, University of Kentucky, Lexington 40536-0082.

Aluminum (Al) has been shown to produce deficits in learning and memory. The present experiments tested the hypothesis that Al-induced inhibition of learning may be due to its effect on glutamate release secondary to changes in calcium channel function and/or intracellular events triggering glutamate release. Calcium-dependent potassium (K)-evoked [14C]-glutamate release from 400 microns transverse rat hippocampal slices was inhibited by Al in a concentration dependent manner (IC50 = 40 microM). Aluminum (30, 100 microM) noncompetitively inhibited Bay K 8644-evoked glutamate release. 4-Aminopyridine (30, 1000 microM) noncompetitively attenuated the Al inhibition of glutamate release, suggesting an Al-induced alteration of Ca channel function. Activation of the Gi protein by R(-)phenylisopropyladenosine (PIA; 1 microM) reduced K-evoked glutamate release 69%, whereas 300 microM Al produced an 84% reduction. These effects were prevented by the Gi protein inhibitor N-ethylmaleimide (NEM; 100 microM), suggesting an effect of Al on the Gi protein to inhibit glutamate release. Phorbol myristate acetate (0.16 microM)-induced glutamate release was inhibited by 300 microM Al and 80 microM polymyxin B, suggesting an Al modulation of protein kinase C (PKC)-evoked glutamate release. These results demonstrate an Al inhibition of glutamate release that may be mediated by multiple, but interconnected mechanisms (e.g., via interactions with Ca systems), providing multiple targets for an Al-induced alteration of neuronal function.
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December 1992
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