Publications by authors named "Sella A Provan"

28 Publications

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The changing states of fibromyalgia in patients with axial spondyloarthritis: results from the British Society of Rheumatology Biologics Register for Ankylosing Spondylitis.

Rheumatology (Oxford) 2021 Sep;60(9):4121-4129

Department of Rheumatology, National Resource Centre for Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objectives: To identify factors associated with FM development and recovery in patients with axial SpA (axSpA).

Methods: The British Society of Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) recruited patients with axSpA from 83 centres in a prospective study. FM was diagnosed using the self-reported Fibromyalgia Survey Diagnostic Criteria from 2015. Measures of axSpA disease activity and clinical findings were recorded at regular intervals. We identified predictors for FM development and recovery between yearly visits using uni- and multivariable logistic regression models.

Results: A total of 801 participants, 247 (30.8%) female, had two or more visits and were eligible for inclusion. A total of 686 participants did not have FM at baseline, of whom 45 had developed FM at follow-up, while 115 participants had FM at baseline, of whom 77 had recovered at follow-up. A high baseline BASDAI score [odds ratio (OR) 1.27 (95% CI 1.08, 1.49)] and Widespread Pain Index (WPI) [OR 1.14 (95% CI 1.02, 1.28)] were significantly associated with FM development in the final multivariable model. A low baseline BASFI score [OR 0.68 (95% CI 0.53, 0.86)] and WPI [OR 0.84 (95% CI 0.720, 0.97)] and starting a TNF inhibitor [OR 3.86 (95% CI 1.54, 9.71)] were significantly associated with FM recovery.

Conclusion: High levels of disease activity and the presence of widespread pain is associated with the development of FM in patients with axSpA, while low levels of the same variables and starting a TNF inhibitor are associated with recovery from FM. The presence of comorbid FM should be considered in patients with persistent high axSpA disease activity and widespread pain.
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http://dx.doi.org/10.1093/rheumatology/keaa888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409995PMC
September 2021

Inflammatory Joint Diseases and Risk of Cardiovascular Disease in Modern Rheumatology.

J Rheumatol 2021 03;48(3):311-313

I.J. Berg, MD, PhD, Consultant Rheumatologist; S.A. Provan, MD, PhD Associate Professor, Consultant Rheumatologist, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

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http://dx.doi.org/10.3899/jrheum.201134DOI Listing
March 2021

Viral respiratory infections in patients treated with hydroxychloroquine.

Clin Exp Rheumatol 2021 Sep-Oct;39(5):1146. Epub 2021 Apr 7.

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

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April 2021

Effectiveness of a Second Biologic After Failure of a Non-tumor Necrosis Factor Inhibitor As First Biologic in Rheumatoid Arthritis.

J Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

This study was partly funded by grants from Nord-Forsk and FOREUM.
K. Chatzidionysiou, MD, PhD, Associate Professor, T. Frisell, PhD, Associate Professor, D. Di Giuseppe, PhD, K. Hellgren, MD, PhD, J. Askling, MD, PhD, Professor, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; M.L. Hetland, MD, PhD, Professor, B. Glintborg, MD, PhD, Associate Professor, DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, on behalf of the DANBIO Registry, Copenhagen, Denmark; D. Nordström, MD, PhD, Professor, R. Peltomaa, MD, PhD, N. Trokovic, MS, Helsinki University and Hospital (ROB-FIN), Departments of Medicine and Rheumatology, Helsinki, Finland; K. Aaltonen, MD, PhD, Pharmaceuticals Pricing Board, Ministry of Social Affairs and Health, Helsinki, Finland; E.K. Kristianslund, MD, PhD, T.K. Kvien, MD, PhD, Professor, S.A. Provan, MD, PhD, Professor, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway; B. Gudbjornsson, MD, PhD, Professor, Centre for Rheumatology Research, University Hospital, and Faculty of Medicine, University of Iceland, Reykjavik, Iceland; G. Grondal, MD, PhD, Professor, Department of Rheumatology and Centre for Rheumatology Research, University Hospital, Reykjavik, Iceland; L. Dreyer, MD, PhD, Professor, Department of Rheumatology, Aalborg University Hospital, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; L.E. Kristensen, MD, PhD, Professor, T.S. Jørgensen, MD, PhD, The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark; L.T. Jacobsson, MD, PhD, Professor, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. KC has received consultancy fees from Eli Lilly, AbbVie, and Pfizer. MLH has received grant/research support from BMS, MSD, AbbVie, Roche, Novartis, Biogen, and Pfizer; consultancy fees from Eli Lilly; and speaker's fees from Orion Pharma, Biogen, Pfizer, CellTrion, Merck, and Samsung Bioepis. DN has received consultancy fees from AbbVie, BMS, Celgene, MSD, Novartis, Pfizer, Roche, and UCB. BjG has received speaker fees from Novartis. TKK has received consulting fees, speaking fees, and/or honoraria from AbbVie, Amgen, Biogen, BMS, Celtrion, Egis, Eli Lilly, Evapharma, Ewopharma, Janssen, MSD, Mylan, Oktal Pharma, Orion Pharma, Pfizer, Roche, Sandoz, Sanofi, and UCB Pharma. LD has received grant/research support from BMS; consultancy fees from Janssen pharmaceuticals; and speaker's fees from Eli Lilly, UCB, and MSD. LEK has received consulting fees, speaking fees and/or honoraria from AbbVie, Amgen, Biogen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, and UCB Pharma. TSJ has received consulting fees and/or speaking fees from AbbVie, Pfizer, Roche, Novartis, UCB, Biogen, and Eli Lilly. JA (as the principal investigator) and the Karolinska Institutet have entered into agreements with the following companies mainly regarding the safety monitoring of b/tsDMARDs in rheumatology: AbbVie, BMS, MSD, Eli Lilly, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. The remaining authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. K. Chatzidionysiou, Rheumatology Unit, Karolinska University Hospital, D2:00, 171 76, Solna, Stockholm, Sweden. Email: Accepted for publication February 19, 2021.

Objective: In rheumatoid arthritis (RA), evidence regarding the effectiveness of a second biologic disease- modifying antirheumatic drug (bDMARD) in patients whose first-ever bDMARD was a non-tumor necrosis factor inhibitor (TNFi) bDMARD is limited. The objective of this study was therefore to assess the outcome of a second bDMARD (non-TNFi: rituximab [RTX], abatacept [ABA], or tocilizumab [TCZ], separately; and TNFi) after failure of a non-TNFi bDMARD as first bDMARD.

Methods: We identified patients with RA from the 5 Nordic biologics registers who started treatment with a non-TNFi as first-ever bDMARD but switched to a second bDMARD. For the second bDMARD, we assessed drug survival (at 6 and 12 months) and primary response (at 6 months).

Results: We included 620 patients starting a second bDMARD (ABA 86, RTX 40, TCZ 67, and TNFi 427) following failure of a first non-TNFi bDMARD. At 6 and 12 months after start of their second bDMARD, approximately 70% and 60%, respectively, remained on treatment, and at 6 months, less than one-third of patients were still on their second bDMARD and had reached low disease activity or remission according to the Disease Activity Score in 28 joints. For those patients whose second bMDARD was a TNFi, the corresponding proportion was slightly higher (40%).

Conclusion: The drug survival and primary response of a second bDMARD in patients with RA switching due to failure of a non-TNFi bDMARD as first bDMARD is modest. Some patients may benefit from TNFi when used after failure of a non-TNFi as first bDMARD.
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http://dx.doi.org/10.3899/jrheum.201467DOI Listing
March 2021

The changing states of fibromyalgia in patients with axial spondyloarthritis: results from BSRBR-AS.

Rheumatology (Oxford) 2021 Jan 6. Epub 2021 Jan 6.

Department of Rheumatology, National Resource Centre for Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objectives: To identify factors associated with fibromyalgia (FM) development and recovery in patients with axial spondyloarthritis (axSpA).

Methods: The British Society of Rheumatology Biologics Register (BSRBR-AS) recruited patients with axSpA from 83 centres, in a prospective study. FM was diagnosed using the self-reported Fibromyalgia Survey Diagnostic Criteria (FM-criteria) from 2015. Measures of axSpA disease activity and clinical findings were recorded at regular intervals. We identified predictors for FM development and recovery between yearly visits using uni- and multivariable logistic regression models.

Results: Eight hundred and one participants, 247 (30.8%) female, had two or more visits and were eligible for inclusion. 686 participants did not have FM at baseline, of whom 45 had developed FM at follow-up. 115 participants had FM at baseline, of whom 77 had recovered at follow-up. High baseline Bath Ankylosing Disease activity Index (OR 1.27, 95% CI 1.08-1.49) and Widespread pain index (WPI) (OR 1.14, 95% CI 1.02-1.28) were significantly associated withFM development in the final multivariable model. Low baseline Bath Ankylosing Function Index (OR 0.68, 95% CI 0.53-0.86), WPI (OR 0.84, 95% CI 0.720 to 0.97) and starting a tumour necrosis factor (TNF) inhibitor(OR 3.86, 95% CI 1.54-9.71) were significantly associated with FM recovery.

Conclusion: High levels of disease activity and presence of widespread pain is associated with the development of FM in patients with axSpA, while low levels of the same variables and starting a TNF-inhibitor are associated with recovery from FM. The presence of co-morbid FM should be considered in patients with persistent high axSpA disease activity and wide spread pain.
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http://dx.doi.org/10.1093/rheumatology/keaa888DOI Listing
January 2021

Fatigue is cross-sectionally not associated with objective assessments of inflammation, but changes in fatigue are associated with changes of disease activity assessments during biologic treatment of patients with established rheumatoid arthritis.

Clin Rheumatol 2021 May 11;40(5):1739-1749. Epub 2020 Oct 11.

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

Objective: The associations between fatigue and disease activity in patients with rheumatoid arthritis (RA) have not been defined. The present objectives were to explore in RA patients the cross-sectional and longitudinal relation of fatigue with subjective as well as objective assessments of disease activity.

Methods: RA patients were consecutively included when initiating biologic disease-modifying anti-rheumatic drugs (DMARDs) and assessed at baseline, 1, 2, 3, 6, and 12 months with investigation of fatigue, patient-reported outcome measures (PROMs; joint pain and patient's global disease activity, MHAQ, pain catastrophizing, Mental Health score), clinical examinations (examiner's global disease activity, 28 tender and swollen joint counts), and laboratory variables (ESR, CRP, calprotectin). Ultrasound examinations (semi-quantitative scoring (0-3)) with grey scale and power Doppler were performed of 36 joints and 4 tendons. Statistics included one-way analysis of variance, Pearson's correlations, and multiple linear and logistic regression analysis.

Results: A total of 208 RA patients (mean (SD) age 53.2 (13.2) years, disease duration 9.8 (8.5) years) were included. Fatigue levels diminished during follow-up (mean (SD) baseline/12 months; 4.8 (2.8)/3.0 (2.5) (p < 0.001)). Substantial correlations were cross-sectionally found between fatigue and PROMs (median (IQR) r=0.61 (0.52-0.71)) but not with the objective inflammatory assessments. During follow-up, baseline fatigue was associated with PROMs (p < 0.001) but not with objective inflammatory assessments. However, change of fatigue was associated with change in all variables. Higher baseline fatigue levels were associated with lower clinical composite score remission rates.

Conclusion: Fatigue was cross-sectionally associated to subjective but not to objective disease assessments. However, change of fatigue during treatment was associated to all assessments of disease activity.

Trial Registration Number: Anzctr.org.au identifier ACTRN12610000284066, Norwegian Regional Committee for Medical and Health Research Ethics South East reference number 2009/1254 Key Points • In this longitudinal study of patients with established RA, fatigue was associated with patient reported outcome measures at each visit, but not with objective assessments of inflammation including calprotectin and comprehensive ultrasound examinations. • Changes in fatigue during biological treatment were associated with changes in patient reported outcome measures, clinical, laboratory and ultrasound assessments. • Baseline fatigue was associated with all patient reported outcome measures, but not objective assessments of inflammation at all the prospective visits. • Higher baseline fatigue levels were associated with lower remission rates as assessed by clinical composite scores.
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http://dx.doi.org/10.1007/s10067-020-05402-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102439PMC
May 2021

Inflammatory hallmarks of lesser prominence in psoriatic arthritis patients starting biologics: a Nordic population-based cohort study.

Rheumatology (Oxford) 2021 01;60(1):140-146

Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen.

Objectives: To assess secular trends in baseline characteristics of PsA patients initiating their first or subsequent biologic DMARD (bDMARD) therapy and to explore prescription patterns and treatment rates of bDMARDs from 2006 to 2017 in the Nordic countries.

Methods: PsA patients registered in the Nordic rheumatology registries initiating any treatment with bDMARDs were identified. The bDMARDs were grouped as original TNF inhibitor [TNFi; adalimumab (ADA), etanercept (ETN) and infliximab (IFX)]; certolizumab pegol (CZP) and golimumab (GOL); biosimilars and ustekinumab, based on the date of release. Baseline characteristics were compared for the five countries, supplemented by secular trends with R2 calculations and point prevalence of bDMARD treatment.

Results: A total of 18 089 patients were identified (Denmark, 4361; Iceland, 449; Norway, 1948; Finland, 1069; Sweden, 10 262). A total of 54% of the patients were female, 34.3% of patients initiated an original TNFi, 8% CZP and GOL, 7.5% biosimilars and 0.3% ustekinumab as a first-line bDMARD. Subsequent bDMARDs were 25.2% original TNFi, 9% CZP and GOL, 12% biosimilars and 2.1% ustekinumab. From 2015 through 2017 there was a rapid uptake of biosimilars. The total of first-line bDMARD initiators with lower disease activity increased from 2006 to 2017, where an R2 close to 1 showed a strong association.

Conclusion: Across the Nordic countries, the number of prescribed bDMARDs increased from 2006 to 2017, indicating a previously unmet need for bDMARDs in the PsA population. In recent years, PsA patients have initiated bDMARDs with lower disease activity compared with previous years, suggesting that bDMARDs are initiated in patients with a less active inflammatory phenotype.
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http://dx.doi.org/10.1093/rheumatology/keaa237DOI Listing
January 2021

Trends in all-cause and cardiovascular mortality in patients with incident rheumatoid arthritis: a 20-year follow-up matched case-cohort study.

Rheumatology (Oxford) 2020 03;59(3):505-512

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objectives: To examine all-cause and cardiovascular disease (CVD) mortality in consecutive cohorts of patients with incident RA, compared with population comparators.

Methods: The Oslo RA register inclusion criteria were diagnosis of RA (1987 ACR criteria) and residency in Oslo. Patients with disease onset 1994-2008 and 10 matched comparators for each case were linked to the Norwegian Cause of Death Registry. Hazard ratios for all-cause and CVD mortality were calculated for 5, 10, 15 and 20 years of observation using stratified cox-regression models. Mortality trends were estimated by multivariate cox-regression.

Results: 443, 479 and 469 cases with disease incidence in the periods 94-98, 99-03 and 04-08 were matched to 4430, 4790 and 4690 comparators, respectively. For cases diagnosed between 1994 and 2003, the all-cause mortality of cases diverged significantly from comparators after 10 years of disease duration [hazard ratio (95% CI) 94-98 cohort 1.42 (1.15-1.75): 99-03 cohort 1.37 (1.08-1.73)]. CVD related mortality was significantly increased after 5 years for the 94-98 cohort [hazard ratio (95% CI) 1.86 (1.16-2.98) and after 10 years for the 99-03 cohort 1.80 (1.20-2.70)]. Increased mortality was not observed in the 04-08 cohort where cases had significantly lower 10-year all-cause and CVD mortality compared with earlier cohorts.

Conclusion: All-cause and CVD mortality were significantly increased in RA patients diagnosed from 1994 to 2003, compared with matched comparators, but not in patients diagnosed after 2004. This may indicate that modern treatment strategies have a positive impact on mortality in patients with RA.
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http://dx.doi.org/10.1093/rheumatology/kez371DOI Listing
March 2020

Swollen, but not tender joints, are independently associated with ultrasound synovitis: results from a longitudinal observational study of patients with established rheumatoid arthritis.

Ann Rheum Dis 2019 09 6;78(9):1179-1185. Epub 2019 Jun 6.

Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objectives: Joint swelling and tenderness are considered a proxy for inflammation in patients with rheumatoid arthritis (RA). With ultrasound-detected inflammation as reference, our objectives were to explore on patient and joint level the associations between ultrasound synovitis and joint swelling, tenderness and patient-reported joint pain (PRJP).

Methods: 209 patients with established RA were examined six times during 12 months with assessment of 32 joints in upper/lower extremities for joint swelling/tenderness and Grey scale (GS)/power Doppler (PD) synovitis. PRJP was assessed on a manikin. Correlations between different sum scores were at each examination calculated using Spearman's rho (r), agreement at joint level was examined by Cohen's kappa and logistic regression models were used to explore the associations between joint assessment and GS/PD scores.

Results: At patient level, swollen joints were strongly correlated with GS/PD sum scores (r=0.64-0.88), while tender joints were primarily associated with PRJP (r=0.54-0.68). At joint level, GS/PD pathology had higher agreement with swelling (kappa 0.54-0.57) than tenderness (kappa 0.20-0.21) or PRJP (0.23-0.25). Higher percentages of joints were swollen according to increasing GS/PD scores, independently of joint tenderness. However, joints being tender, but not swollen, were not associated with GS/PD scores. Receiver operating curves showed swollen but not tender joints to be associated with GS/PD scores.

Conclusions: Swollen joints were strongly associated with ultrasound detected synovitis at both patient and joint level, while this association was not found for tender joints. These results may question if tender joints reflect ongoing inflammation in established RA.
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http://dx.doi.org/10.1136/annrheumdis-2019-215321DOI Listing
September 2019

Tender Joint Count and Inflammatory Activity in Patients With Established Rheumatoid Arthritis: Results From a Longitudinal Study.

Arthritis Care Res (Hoboken) 2020 01;72(1):27-35

Diakonhjemmet Hospital, Oslo, Norway.

Objective: The tender joint count (TJC) is included in composite disease activity scores (CDAS) (the Disease Activity Score in 28 joints, the Clinical Disease Activity Index, and the Simplified Disease Activity Index). The impact of having predominantly tender joints was explored by use of the Tender-Swollen Joint Count Difference (TSJD), and ultrasound (US) provided a measure of joint inflammation. The current study aimed to explore the cross-sectional and longitudinal associations between the TSJD and a spectrum of outcome measures, including US scores in patients with established rheumatoid arthritis (RA) during follow-up and while receiving treatment with biologic disease-modifying antirheumatic drugs (bDMARDs).

Methods: This was an observational study of 209 patients with established RA consecutively included upon initiation of bDMARD treatment and followed-up with clinical, laboratory, and comprehensive US examinations at 0, 1, 2, 3, 6, and 12 months. Patients were categorized into 2 groups: those with predominantly tender joints (TSJD >0) and those with predominantly swollen joints (TSJD ≤0). Statistical analyses included Pearson's correlation coefficient, an independent samples t-test, and regression analyses.

Results: The TJC had high correlations only with patient-reported outcomes (PROMs) (P < 0.001). Levels from CDAS and PROMs were significantly higher (P < 0.001) at all visits in patients with TSJD >0 compared to those with TSJD <0. Laboratory markers and assessor's global visual analog scale scores were similar, and US sum scores were significantly lower (P < 0.001-0.03). The baseline TSJD positively predicted levels of all CDAS at 6 months (P < 0.001-0.019) but was a negative predictor of US sum scores (gray-scale and power Doppler) at 6 and 12 months (P < 0.001).

Conclusion: Patients with predominantly tender joints had higher CDAS but lower levels of inflammation as defined by US. These findings indicate that inclusion of the TJC in the CDAS may contribute to misleading information about inflammatory activity.
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http://dx.doi.org/10.1002/acr.23815DOI Listing
January 2020

Treating Fatigue in Rheumatoid Arthritis: Does Patient Age Matter?

Drugs Aging 2018 10;35(10):871-876

Department of Rheumatology, Diakonhjemmet Hospital, Postbox 23, Vinderen, 0319, Oslo, Norway.

Clinically relevant fatigue is common in patients with rheumatoid arthritis (RA) and might be expected to be related to patient age and disease severity. This review provides a brief introduction to fatigue as a patient-reported outcome that contributes significantly to burden of disease, with a focus on the evidence in elderly patients, and gives an overview of our current understanding of the factors that contribute to fatigue. We summarize the evidence for the effects of pharmacological (disease-modifying anti-rheumatic drugs, DMARDs) and non-pharmacological interventions for fatigue. The underlying pathophysiology of fatigue is complex and often multifactorial. The experience of fatigue varies between individuals, and subtypes of fatigue are increasingly being recognized. Fatigue can therefore be challenging to recognize and quantify. Recent systematic reviews have shown that fatigue can be improved as a result of treatment with traditional and biological anti-rheumatic drugs, and also with non-pharmacological approaches (physical activity, psychosocial interventions). Age does not appear to be of major importance for fatigue in RA, and similar strategies for treating fatigue apply to all age groups, including the elderly.
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http://dx.doi.org/10.1007/s40266-018-0589-4DOI Listing
October 2018

Osteoarthritis-Related Walking Disability and Arterial Stiffness: Results From a Cross-Sectional Study.

Arthritis Care Res (Hoboken) 2019 02;71(2):252-258

Diakonhjemmet Hospital, Oslo, Norway.

Objective: To compare the 6-minute walking distance (6MWD) in a population-based cohort of patients with osteoarthritis (OA) with that in matched peers from the general population, and to explore the associations between walking ability and risk of cardiovascular disease (CVD) in the OA cohort.

Methods: This cross-sectional study included individuals (ages 40-80 years) who had self-reported OA (n = 500) in a previous population-based study and age- and sex-matched peers from the general population (n = 235). Clinical examinations of the patients with OA included classification according to the American College of Rheumatology criteria, blood sampling, and measuring arterial stiffness (PWV; pulse wave velocity). Group differences in the 6MWD were calculated with t-tests. The association between walking ability and CVD risk in the OA cohort was examined using multivariate regression models.

Results: In the age-stratified analyses, the largest mean difference in the 6MWD was observed in the youngest age groups (40-49 years); female patients in the OA group walked 84.6 fewer meters compared with the reference group (579.4 meters and 663.9 meters, respectively; P < 0.001), and male patients walked 88.3 fewer meters compared with the reference group (619.9 meters and 708.3 meters, respectively; P = 0.001). In the OA group, the 6MWD was significantly associated with PWV in the adjusted analysis (P = 0.001); an increase in the walking distance of 100 meters corresponded to a reduction in PWV of 0.3 meters/second.

Conclusion: Even at age 40 years, patients with OA had a significantly shorter mean walking distance compared with their matched peers, underlining the importance of an early clinical approach to OA. Furthermore, in the OA group, the 6MWD was significantly associated with arterial stiffness, suggesting that walking ability is important for the CVD risk profile in patients with OA.
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http://dx.doi.org/10.1002/acr.23697DOI Listing
February 2019

Associations Between Cardiorespiratory Fitness and Arterial Stiffness in Ankylosing Spondylitis: A Cross-sectional Study.

J Rheumatol 2018 11 1;45(11):1522-1525. Epub 2018 Jul 1.

From the Department of Rheumatology, and the Preventive Cardio-Rheuma Clinic, Diakonhjemmet Hospital, Oslo, Norway; the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Objective: To assess associations between cardiorespiratory fitness (CRF), measured as peak oxygen uptake (VOpeak), and cardiovascular disease (CVD) risk, measured by arterial stiffness, in patients with ankylosing spondylitis (AS).

Methods: VOpeak was assessed by a maximal walking test on a treadmill. Arterial stiffness was measured noninvasively (Sphygmocor apparatus). Cross-sectional associations between VOpeak and arterial stiffness were analyzed using backward multivariable linear regression.

Results: Among 118 participating patients, there were significant inverse associations between VOpeak and arterial stiffness, independent of traditional CVD risk factors and measures of disease activity.

Conclusion: Reduced CRF may be related to increased risk of CVD in AS.
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http://dx.doi.org/10.3899/jrheum.170726DOI Listing
November 2018

Opportunities and challenges for real-world studies on chronic inflammatory joint diseases through data enrichment and collaboration between national registers: the Nordic example.

RMD Open 2018 12;4(1):e000655. Epub 2018 Apr 12.

Clinical Epidemiology Section, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

There are increasing needs for detailed real-world data on rheumatic diseases and their treatments. Clinical register data are essential sources of information that can be enriched through linkage to additional data sources such as national health data registers. Detailed analyses call for international collaborative observational research to increase the number of patients and the statistical power. Such linkages and collaborations come with legal, logistic and methodological challenges. In collaboration between registers of inflammatory arthritides in Sweden, Denmark, Norway, Finland and Iceland, we plan to enrich, harmonise and standardise individual data repositories to investigate analytical approaches to multisource data, to assess the viability of different logistical approaches to data protection and sharing and to perform collaborative studies on treatment effectiveness, safety and health-economic outcomes. This narrative review summarises the needs and potentials and the challenges that remain to be overcome in order to enable large-scale international collaborative research based on clinical and other types of data.
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http://dx.doi.org/10.1136/rmdopen-2018-000655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905834PMC
April 2018

Evidence of reduced parasympathetic autonomic regulation in inflammatory joint disease: A meta-analyses study.

Semin Arthritis Rheum 2018 08 5;48(1):134-140. Epub 2017 Dec 5.

Department of Rheumatology, National Resource Centre for Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Background: Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are inflammatory joint disorders (IJD) with increased risk of cardiovascular disease (CVD). Autonomic dysfunction (AD) is a risk factor for CVD, and parasympathetic AD is linked to key features of IJD such as inflammation, physical inactivity and pain. Heart-rate variability (HRV) is a marker of cardiac AD. The study objective was to compare parasympathetic cardiac AD, measured by HRV, between patients with IJD and healthy controls, using meta-analysis methodology, and to examine the impact of inflammation, physical inactivity and pain on HRV in IJD.

Methods: Medline, Embase and Amed were searched. Inclusion criteria were adult case-control studies published in English or a Scandinavian language, presenting HRV data in IJD. Two measures of HRV and 3 from the Ewing protocol were selected: square root of mean squared difference of successive R-R intervals (RMSSD), high frequency (HF), Ewing protocol; standing (E-S), breathing (E-B) and Valsalva (E-V). Patients with RA, SpA and healthy controls were compared separately using random-effects meta-analyses of standardized mean differences (SMD).

Results: In all, 35 papers were eligible for inclusion. For RMSSD the pooled SMD (95% CI) RA vs. controls was -0.90 (-1.35 to -0.44), for SpA vs. controls; -0.34 (-0.73 to 0.06). For HF pooled SMD RA vs. controls was -0.78 (-0.99 to -0.57), for SpA vs. controls; -0.04 (-0.22 to 0.13). All Ewing parameters were significantly lower in cases, except for E-V which was comparable between cases and controls in patients with RA.

Conclusion: Patients with IJD have cardiac parasympathetic AD which is related to inflammation.
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http://dx.doi.org/10.1016/j.semarthrit.2017.11.010DOI Listing
August 2018

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

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

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

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

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

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

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

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
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