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  • 151. Holmqvist, Marie
    et al.
    Gransmark, Emma
    Mantel, Angla
    Alfredsson, Lars
    Jacobsson, Lennart T. H.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Askling, Johan
    Occurrence and relative risk of stroke in incident and prevalent contemporary rheumatoid arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no 4, p. 541-546Article in journal (Refereed)
    Abstract [en]

    Objective In contrast with the wealth of data on ischaemic heart disease in rheumatoid arthritis (RA), data on stroke are scarce and contradictory. Despite the high clinical and aetiological relevance, there is no data regarding when (if ever) after RA diagnosis there is an increased risk. Our objective was to assess the risk of stroke (by subtype) in contemporary patients with RA, particularly in relation to time since RA diagnosis. Methods One incident RA cohort diagnosed between 1997 and 2009 (n=8077) and one nationwide prevalent RA cohort followed at Swedish rheumatology clinics between 2005 and 2009 ((n=39065) were assembled). Each cohort member was matched to a general population comparator. Information on first-time hospitalisations for stroke up to 2009 was retrieved from the Swedish Patient Register. HR and 95% CI were estimated using Cox models. Results In prevalent unselected RA, the HR of ischaemic stroke was 1.29 (95% CI 1.18 to 1.41). In the incident RA cohort, the overall risk increase was small and nonsignificant (overall HR 1.11, 95% CI 0.95 to 1.30). When stratified by RA disease duration, an increased risk of ischaemic stroke was indeed detectable but only after 10 or more years since RA diagnosis (HR>10 years: 2.33, 95% CI 1.25 to 4.34). Risk of haemorrhagic stroke was increased in prevalent but not in incident RA. Conclusion The magnitude of stroke risk is lower than for ischaemic heart disease in RA, and the evolvement of this risk from RA diagnosis may be slower. This suggests different driving forces behind these two RA co-morbidities and has implications for the clinical follow-up of patients with RA.

  • 152. Holmqvist, Marie
    et al.
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Askling, Johan
    Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 10, p. 1642-1647Article in journal (Refereed)
    Abstract [en]

    Background Acute coronary syndrome (ACS) and other cardiovascular diseases are the main drivers of the increased morbidity and preterm mortality in rheumatoid arthritis (RA). ACS in RA has been linked to inflammation and RA severity. During recent years and with new therapeutic options and treat-to-target strategies, increasing efforts have been made to reach RA remission as soon as possible after diagnosis, and the average level of RA disease activity has declined. Whether this has resulted in declining excess risks for RA comorbidities remains unclear. Methods We performed a nationwide population-based cohort study of patients with new-onset RA from 1997 to 2014, and matched general population comparators. In the Swedish healthcare system, all residents have equal access to healthcare services. Healthcare is monitored using high-quality population-based registers that can be linked together. 15 744 patients with new-onset RA, identified from the Swedish Rheumatology Quality Register, and 70 899 general population comparator subjects were included. Results Seven hundred and seventy two patients with RA developed an ACS during 103 835 person-years of follow-up (crude incidence, 7.4 per 1000), corresponding to an overall HR versus the general population of 1.41 (95% CI 1.29 to 1.54). Whereas the ACS incidence declined over calendar time in both the RA and the general population cohort, the excess and the relative risks of ACS remained the same. Conclusions D espite improved disease control in new-onset RA, the elevated risk of ACS in RA remains a concern.

  • 153. Holmqvist, Marie
    et al.
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Askling, Johan
    Mortality following new-onset Rheumatoid Arthritis: has modern Rheumatology had an impact?2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 1, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate if, and when, patients diagnosed with rheumatoid arthritis (RA) in recent years are at increased risk of death. Methods: Using an extensive register linkage, we designed a population-based nationwide cohort study in Sweden. Patients with new-onset RA from the Swedish Rheumatology Quality Register, and individually matched comparators from the general population were followed with respect to death, as captured by the total population register. Results: 17 512 patients with new-onset RA between 1 January 1997 and 31 December 2014, and 78 847 matched general population comparator subjects were followed from RA diagnosis until death, emigration or 31 December 2015. There was a steady decrease in absolute mortality rates over calendar time, both in the RA cohort and in the general population. Although the relative risk of death in the RA cohort was not increased (HR=1.01, 95% CI 0.96 to 1.06), an excess mortality in the RA cohort was present 5 years after RA diagnosis (HR after 10 years since RA diagnosis=1.43 (95% CI 1.28 to 1.59)), across all calendar periods of RA diagnosis. Taking RA disease duration into account, there was no clear trend towards lower excess mortality for patients diagnosed more recently. Conclusions: Despite decreasing mortality rates, RA continues to be linked to an increased risk of death. Thus, despite advancements in RA management during recent years, increased efforts to prevent disease progression and comorbidity, from disease onset, are needed.

  • 154.
    Holmqvist, ME
    et al.
    Institute of Environmental Medicine, Karolinska Institutet.
    Wedren, S
    Institute of Environmental Medicine, Karolinska Institutet.
    Jacobsson, LTH
    Rheumatology Unit, Department of Medicine, Malmö University Hospital, Malmö.
    Klareskog, L
    Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska Hospital, Stockholm.
    Nyberg, F
    Institute of Environmental Medicine, Karolinska Institutet.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Alfredsson, L
    Institute of Environmental Medicine, Karolinska Institutet.
    Askling, J
    Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska Hospital, Stockholm.
    Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 20062010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 268, no 6, p. 578-585Article in journal (Refereed)
    Abstract [en]

    Holmqvist ME, Wedren S, Jacobsson LTH, Klareskog L, Nyberg F, Rantapaa-Dahlqvist S, Alfredsson L, Askling J (Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Karolinska Institutet/Karolinska Hospital, Stockholm; Malmo University Hospital, Malmo; AstraZeneca R&D, Molndal; and Umea University Hospital, Umea, Sweden) Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J Intern Med 2010; 268: 578-585. The risk of ischaemic heart disease (IHD), and in particular myocardial infarction (MI), is increased amongst patients with established rheumatoid arthritis (RA). Few studies have included contemporary patients with RA. We recently reported that the risk of IHD is not elevated before the onset of RA symptoms. However, when, in relation to RA diagnosis, the risk is increased is unknown. Objective. To assess the risk of MI and other IHD events amongst patients diagnosed with RA during the last decade and within 18 months following RA symptom onset, compared to the general population, by time since RA diagnosis, year of RA diagnosis and by rheumatoid factor (RF) status. Methods and patients. A Swedish inception cohort of RA (n = 7469) diagnosed between 1995 and 2006 and a matched general population comparator cohort (n = 37 024), was identified and linked to national registers of morbidity and mortality from IHD. Relative risks (RRs) of MI and other IHD events were estimated using Cox regression. Results. During follow-up, 233 patients with RA and 701 controls developed a first MI, corresponding to an overall RR of MI of 1.6 (95% confidence interval 1.4, 1.9). Increased risks of MI were already detected within 1-4 years following RA diagnosis, as well as in patients diagnosed with RA during the last 5 years, in RF-negative patients and for transmural as well as nontransmural MIs. Conclusions. MI risk increases rapidly following RA diagnosis, suggesting the importance of additional mechanisms other than atherosclerosis. The elevated short-term risk is present amongst patients diagnosed in recent years, underscoring the importance of MI prevention from the time of RA diagnosis.

  • 155. Hom, Geoffrey
    et al.
    Graham, Robert R
    Modrek, Barmak
    Taylor, Kimberly E
    Ortmann, Ward
    Garnier, Sophie
    Lee, Annette T
    Chung, Sharon A
    Ferreira, Ricardo C
    Pant, P V Krishna
    Ballinger, Dennis G
    Kosoy, Roman
    Demirci, F Yesim
    Kamboh, M Ilyas
    Kao, Amy H
    Tian, Chao
    Gunnarsson, Iva
    Bengtsson, Anders A
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Petri, Michelle
    Manzi, Susan
    Seldin, Michael F
    Rönnblom, Lars
    Syvänen, Ann-Christine
    Criswell, Lindsey A
    Gregersen, Peter K
    Behrens, Timothy W
    Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, no 9, p. 900-909Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4are established susceptibility genes; there is strong evidence for the existence of additional risk loci.

    METHODS: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.

    RESULTS: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1×10−10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3×10−11).

  • 156.
    Hörnberg, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Aspects of physical activity in Rheumatoid Arthritis: associations with inflammation and cardiovascular risk factors2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Rheumatoid Arthritis (RA) is associated with an increased risk for cardiovascular disease (CVD), partially attributable to systemic inflammation and traditional risk factors for CVD. Since physical activity (PA) is strongly related to CVD in the general population, the aim of this thesis was to describe aspects of PA in patients with RA, and further to analyse associations with disease activity, traditional risk factors for CVD and subclinical atherosclerosis.

    Methods: In papers I and II, newly diagnosed RA patients were followed for two (n=66) and mean (SD) 16 (2) (n=25) years respectively. Disease activity and aerobic capacity were measured in both groups.​ In paper II, the 25 patients were also examined for traditional risk factors for CVD, body composition, with pulse wave analysis and carotid ultrasound. Self-efficacy was assessed using a questionnaire. In paper III, a combined heart rate and movement monitor was used to measure PA in 84 patients with early (<2 years) and 37 patients with long-standing (mean [SD] 16 [2] years) RA. Data were analysed for associations with disease activity, traditional risk factors for CVD and subclinical atherosclerosis, as above. Finally, in paper IV, a pilot study including 13 patients, median (Q1-Q3) age 57 (44-64) years, was conducted to analyse the feasibility as well as the effects of ten weeks of spinning exercise, on aerobic capacity, traditional risk factors for CVD and inflammation.

    Results: In papers I and II, aerobic capacity was maintained at follow-up. In paper I, median (Q1-Q3) aerobic capacity was 31 (27-39) ml/kg x min at baseline and 33 (25-38) ml/kg x min after two years. In paper II, median (Q1-Q3) aerobic capacity was 32 (28-42) ml/kg x min at baseline and 33 (28-39) ml/kg x min after 16 years. In multiple linear regression analyses, adjusted for baseline aerobic capacity, disease activity during the first two years after diagnosis explained 53 % of the aerobic capacity level after 16 years [b=-0.14, p<0.004]. Higher aerobic capacity was associated with more favourable measures of risk factors for CVD and self-efficacy over time and at follow-up. In paper III, 37 % of the patients with early and 43 % of the patients with long-standing RA, did not reach the national recommendations of PA. Total PA as well as more time spent in moderate to vigorous PA were associated with more favourable risk factors for CVD. Patients with higher disease activity and functional disability were less physically active. In paper IV, intensive spinning exercise proved to be a feasible method, that significantly improved aerobic capacity, systolic blood pressure and the number of tender joints.

    Conclusions: Aerobic capacity, which could be maintained despite several years of disease, was related to risk factors for CVD and to self-efficacy. Higher disease activity in early disease predicted lower aerobic capacity after 16 years. Higher PA level was associated with a more beneficial cardiovascular profile, however, an insufficient level of PA was found in a substantial proportion of patients. Furthermore, we found, that intensive spinning exercise was a feasible method for the group included, to improve aerobic capacity and blood pressure without detrimental effects on disease activity. Physical activity and aerobic capacity have roles to play in the cardio protective management and are, as other modifiable risk factors, suggested to be estimated regularly. Higher disease activity is known to increase the risk of CVD in RA, and as disease activity also seems to negatively impact future aerobic capacity, interventions and support for health enhancing PA should have high priority in these patients. 

  • 157.
    Hörnberg, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Lindström, Britta
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Body function in patients with early rheumatoid arthritis: a 2-year prospective study2007In: Advances in Physiotherapy, ISSN 1403-8196, E-ISSN 1651-1948, Advances in physiotherapy, ISSN 1403-8196, Vol. 9, no 4, p. 144-150Article in journal (Refereed)
    Abstract [en]

    The aim of this prospective study was to analyse joint and muscle function and aerobic capacity over 2 years in a group of patients with early rheumatoid arthritis (RA; i.e. symptomatic for <12 months) in relation to age, pain and disease activity. Sixty-six patients with early RA were followed for 24 months. Joint and muscle function was measured using Signals of Functional Impairment (SOFI) index and aerobic capacity with sub-maximal test on ergometer bicycle. Pain was estimated on Visual Analogue Scale (VAS) and disease activity using 28-joint count Disease Activity Score (DAS 28). Joint and muscle function was impaired in almost all patients at inclusion and after 24 months. Male patients were more affected compared with females and the significant correlation with pain and DAS 28 decreased over time. Aerobic capacity was maintained and not influenced by sex, age or pain but related significantly to disease activity. The majority of the patients with early RA had impairments of the joint and muscle function over 24 months, even though disease activity decreased significantly. There is a need for regular evaluations of physical functions besides disease activity to prevent continuous development of functional losses.

  • 158.
    Hörnberg, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Pomeroy, Jeremy
    Center for Clinical Epidemiology and Population Health, Marshfield, US.
    Sandberg, Camilla
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sundström, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ångström, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Physical activity in early and long-standing RA: relations to disease activity, cardiovascular risk factors and subclinicalatherosclerosisManuscript (preprint) (Other academic)
    Abstract [en]

    Background: The excess risk for cardiovascular disease (CVD) in Rheumatoid Arthritis (RA), is partly attributable to traditional cardiovascular risk factors for CVD and systemic inflammation, factors known to be modified by physical activity.

    Objectives: The aim of this cross-sectional study was to objectively measure and compare the level of physical activity in patients with early and long-standing RA, and to investigate its associations with disease activity, risk factors for CVD and measures of subclinical atherosclerosis.

    Methods: This study included 84 patients with early and 37 with long-standing RA (disease duration, mean [SD] 1.4 [0.4] and 16.3 [2.3] years respectively). Physical activity was measured using a combined accelerometer and heart rate monitor and included total physical activity (counts /min), proportion of moderate to vigorous physical activity (MVPA) and sedentary time. Further assessments were; disease activity (Erythrocyte sedimentation rate [ESR], Disease activity score [DAS28]), functional ability (Health Assessment Questionnaire [HAQ]), risk factors for CVD (blood lipids, i.e., triglycerides, high density lipoprotein [HDL], low density protein [LDL], blood glucose, blood pressure, waist circumference, body mass index [BMI]), body fat and subclinical atherosclerosis (pulse wave velocity [PWV], augmentation index [AIx] and carotid intima-media thickness [cIMT]).

    Results: Physical activity variables did not differ between patients with early and long-standing RA. Thirty- seven % of the patients with early and 43% of the patients with long-standing RA did not reach WHOs recommended levels of MVPA. Univariate linear regression analyses with the two groups combined, showed associations between total physical activity and younger age, lower values for HAQ and ESR, as well as more beneficial values for blood glucose, triglycerides, waist circumference, BMI, body fat, sleeping heart rate (SHR), systolic and diastolic blood pressure, aortic blood pressure and pulse pressure (PP), AIx, PWV, and cIMT. After adjusting each variable for age, sex, disease duration and Actiheart wear time, associations remained for all variables except triglycerides, aortic PP, PWV, AIx and cIMT. In a final regression model, the association with ESR was no longer evident. More time spent in MVPA was associated with younger age and with favourable values of blood glucose, HDL, LDL, waist circumference, SHR and PWV. After the same adjustments, associations remained for HAQ, HDL, blood glucose and SHR.

    Conclusions: Physical activity behaviour was similar in patients with early and long-standing RA. Total physical activity as well as more time spent in moderate to vigorous physical activity were associated with more favourable risk factors for CVD and measures of subclinical atherosclerosis. Patients with lower functional ability were less physically active. These results stress the importance of promoting physical activity in patients with RA. 

  • 159.
    Hörnberg, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Sundström, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Innala, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Aerobic capacity over 16 years in patients with rheumatoid arthritis: relationship to disease activity and risk factors for cardiovascular disease2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190211Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to analyse the change in aerobic capacity from disease onset of rheumatoid arthritis (RA) over 16.2 years, and its associations with disease activity and cardiovascular risk factors. Twenty-five patients (20 f/5 m), diagnosed with RA 1995-2002 were tested at disease onset and after mean 16.2 years. Parameters measured were: sub-maximal ergometer test for aerobic capacity, functional ability, self-efficacy, ESR, CRP and DAS28. At follow-up, cardiovascular risk factors were assessed as blood lipids, glucose concentrations, waist circumference, body mass index (BMI), body composition, pulse wave analysis and carotid intima-media thickness. Aerobic capacity [median (IQR)] was 32.3 (27.9-42.1) ml O2/kg x min at disease onset, and 33.2 (28.4-38.9) at follow-up (p>0.05). Baseline aerobic capacity was associated with follow-up values of: BMI (rs = -.401, p = .047), waist circumference (rs = -.498, p = .011), peripheral pulse pressure (rs = -.415, p = .039) self-efficacy (rs = .420, p = .037) and aerobic capacity (rs = .557, p = .004). In multiple regression models adjusted for baseline aerobic capacity, disease activity at baseline and over time predicted aerobic capacity at follow-up (AUC DAS28, 0-24 months; β = -.14, p = .004). At follow-up, aerobic capacity was inversely associated with blood glucose levels (rs = -.508, p = .016), BMI (rs = -.434, p = .030), body fat% (rs = -.419, p = .037), aortic pulse pressure (rs = -.405, p = .044), resting heart rate (rs = -.424, p = .034) and self-efficacy (rs = .464, p = .020) at follow-up. We conclude that the aerobic capacity was maintained over 16 years. High baseline aerobic capacity associated with favourable measures of cardiovascular risk factors at follow-up. Higher disease activity in early stages of RA predicted lower aerobic capacity after 16.2 years.

  • 160.
    Hörnberg, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ångström, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Benefits of spinning exercise on cardiovascular risk factors in rheumatoid arthritis: a pilot study2014In: Cardiopulmonary Physical Therapy Journal, ISSN 1541-7891, Vol. 25, no 3, p. 68-74Article in journal (Refereed)
    Abstract [en]

    Purpose: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). Exercise is known to reduce this risk in the general population but the cardiovascular effects in patients with RA need further study. The purpose of this pilot study was to examine the effects of spinning exercise on the traditional risk factors for CVD, aerobic capacity and inflammation in patients with RA.

    Methods: Thirteen subjects (12 females, 1 male; median age 57 years) attended intensive spinning sessions lasting 45 minutes, 3 times per week for 10 weeks. Measurements at baseline and at 10 and 25 weeks were aerobic capacity, pulse wave analysis with aortic and peripheral blood pressure (BP), disease activity (CRP, ESR, tender and swollen joints and global health assessment), blood lipid levels, body mass index (BMI), functional ability, and subjective diary notes. Friedman's test and the paired Wilcoxon rank sum test were used to measure changes over time. Correlation analyses were made by the Spearman rank correlation method.

    Results: There were significant improvements over time in aerobic capacity, systolic BP, BMI and tender joint count (p<0.05). After 10 weeks the subjects showed significant improvements in terms of aerobic capacity (+7 ml O2/kg x min; p<0.05), systolic BP (-10.8 mm Hg; p<0.01) and tender joint count (p<0.05). After 25 weeks there was still a significant improvement in systolic BP (p<0.05) compared to baseline.

    Conclusions: Intensive spinning exercise for 10 weeks induced a clinically relevant improvement in aerobic capacity and BP. No detrimental effect on disease activity was recorded.

  • 161. Hüffmeier, Ulrike
    et al.
    Uebe, Steffen
    Ekici, Arif B
    Bowes, John
    Giardina, Emiliano
    Korendowych, Eleanor
    Juneblad, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Apel, Maria
    McManus, Ross
    Ho, Pauline
    Bruce, Ian N
    Ryan, Anthony W
    Behrens, Frank
    Lascorz, Jesús
    Böhm, Beate
    Traupe, Heiko
    Lohmann, Jörg
    Gieger, Christian
    Wichmann, Heinz-Erich
    Herold, Christine
    Steffens, Michael
    Klareskog, Lars
    Wienker, Thomas F
    Fitzgerald, Oliver
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    McHugh, Neil J
    Novelli, Giuseppe
    Burkhardt, Harald
    Barton, Anne
    Reis, André
    Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 11, p. 996-999Article in journal (Refereed)
    Abstract [en]

    Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

  • 162. Imgenberg-Kreuz, J.
    et al.
    Leonard, D.
    Almlof, J. Carlsson
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Bengtsson, A.
    Jonsen, A.
    Padyukov, L.
    Gunnarsson, I.
    Svenungsson, E.
    Sjowall, C.
    Syvanen, A.
    Ronnblom, L.
    Nordmark, G.
    Sandling, J.
    Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 3-3Article in journal (Other academic)
  • 163. Imgenberg-Kreuz, Juliana
    et al.
    Almlof, Jonas Carlsson
    Leonard, Dag
    Alexsson, Andrei
    Nordmark, Gunnel
    Eloranta, Maija-Leena
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Bengtsson, Anders A.
    Jonsen, Andreas
    Padyukov, Leonid
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Sjowall, Christopher
    Ronnblom, Lars
    Syvanen, Ann-Christine
    Sandling, Johanna K.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLADQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 164.
    Innala, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Early rheumatoid arthritis aspects of severity and co-morbidity2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated.

    Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (<58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed.

    Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years.

    Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

  • 165.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Smedby, Torgny
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Magnusson, Staffan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study2014In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 16, no 2, p. R94-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Disease activity, severity and co-morbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in early disease.

    METHODS: In this study, 950 RA patients were followed regularly from inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender/swollen joints, visual analogue scale (VAS) pain/global, disease activity score (DAS28)) and function (health assessment questionnaire (HAQ)). Disease severity, measured by radiographs of hands/feet (erosions, Larsen score), extra-articular disease, nodules and co-morbidities and treatment (disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, biologics, nonsteroidal anti-inflammatory drugs (NSAIDs)) were recorded at inclusion and after 5 years. Autoantibodies (rheumatoid factor (RF), anti-nuclear antibodies (ANA), antibodies against cyclic citrullinated peptides (ACPA)) and genetic markers (human leukocyte antibody (HLA)-shared epitope, protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analyzed at inclusion. Data were stratified as young (YORA) and late (LORA) onset RA, defined as being below/above median age (58 years) at onset.

    RESULTS: LORA was associated with lower frequency of ACPA (P <0.05) and carriage of PTPN22-T variant (P <0.01), but with greater disease activity at inclusion measured as ESR (P < 0.001), CRP (P <0.01) and accumulated disease activity (area under the curve for DAS28) at 6 (P <0.01), 12 (P <0.01) and 24 months (P <0.05), and a higher HAQ score (P <0.01) compared with YORA. At baseline and 24 months, LORA was more often associated with erosions (P <0.01 for both) and a higher Larsen score (P <0.001 for both). LORA was more often treated with corticosteroids (P <0.01), less often with methotrexate (P <0.001) and biologics (P <0.001). YORA was more often associated with early DMARD treatment (P <0.001). Multiple regression analyses supported our findings regarding impact of age on chosen treatment.

    CONCLUSION: YORA patients were more frequently ACPA-positive. LORA was more often associated with erosions, higher Larsen scores, disease activity and HAQ at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and with less DMARDs in early disease. This could have implications for development of co-morbidities.

  • 166.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Jidell, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides2008In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 35, no 6, p. 1002-1008Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA).

    METHODS: The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score.

    RESULTS: Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), and significantly increased area under the curve (AUC) for DAS28 (p < 0.05), ESR (p < 0.01), C-reactive protein (p < 0.01), and swollen joint count (p = 0.057) compared to those without. Corresponding differences were not found in patients with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression (p < 0.0001-0.01) and radiological outcome (p < 0.0001-0.01) at 24 months were significantly predicted by all ACPA after baseline adjustments. PTPN22 T variant and HLA-DRB1 alleles were not related to radiological progression or inflammatory activity over time.

    CONCLUSION: Anti-MCV antibodies are associated with a more severe RA disease, as measured by DAS28, ESR, and swollen joint count over time, compared with anti-CCP2, CCP3, and CCP3.1 antibodies. Radiological progression was predicted equally by all 4 autoantibodies.

  • 167.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Magnusson, Staffan
    Smedby, Torgny
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Öhman, Marie-Louise
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Cardiovascular events in early rheumatoid arthritis (RA) are a result of inflammatory burden and traditional risk factors: a five year prospective study2011In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, no 4, p. R131-Article in journal (Refereed)
    Abstract [en]

    Introduction Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first 5 years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the 5 year follow-up period and the modulatory effect of pharmacological treatment.

    Methods All patients from the four northern-most counties of Sweden with early RA are since December 1995 consecutively recruited at diagnsosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the 5-year follow-up (T5).

    Result Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% ( p<0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5%(p<0.01) whilst smoking decreased from 29.8 to 22.4 % ( p<0.001) and the BMI from 26.3 to 25.8( p<0.05) , respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (AUC DAS28), extra-articular disease, corticosteroid use, shorter duration of treatment with DMARDs and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised ESR at inclusion and AUC DAS28 at 6 months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.

    Conclusion The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

  • 168.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Smedby, Torgny
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Magnusson, Staffan
    Berglin, Ewa H
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Age at onset determines severity and choice of treatment in early rheumatoid arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. S908-S908Article in journal (Refereed)
  • 169.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sjöberg, C.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Berglin, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Magnusson, S.
    Moller, B.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Smedby, T.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Comorbidity in early rheumatoid arthritis - which is the role of inflammation?2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, p. 406-406Article in journal (Other academic)
  • 170.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sjöberg, C
    Möller, B
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Smedby, T
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Magnusson, S
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Comorbidity in patients with early rheumatoid arthritis: does inflammation matter?Manuscript (preprint) (Other academic)
  • 171.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sjöberg, Clara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Berglin, Ewa H
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Rantapää-Dahlqvist, Solbritt M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Comorbidity in early rheumatoid arthritis: does inflammation matter?2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, p. S176-S176, Meeting Abstract: 408Article in journal (Refereed)
  • 172.
    Innala, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sjöberg, Clara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Smedby, Torgny
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Magnusson, Staffan
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Co-morbidity in patients with early rheumatoid arthritis - inflammation matters2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 33Article in journal (Refereed)
    Abstract [en]

    Background: Patients with rheumatoid arthritis (RA) suffer from co-morbidities that contribute to a shortened lifespan. Inflammation is important for the development of cardiovascular disease, but little is known on its relationship with other co-morbidities. We investigated the role of inflammation for the development of new comorbidities in early RA. Methods: Since 1995, all patients with early RA in Northern Sweden are included in a prospective study on comorbidities, with a total of 950 patients being included. At the time for this study, 726 had been ill for >= 5 years. Data on co-morbidities, clinical and laboratory disease activity and pharmacological therapy were collected from patient records and further validated using a questionnaire at RA onset (T0) and after 5 years (T5). Results: Of the patients, 53.2 % of the patients had one or more co-morbidity at onset, the commonest being: hypertension (27.3 %), obstructive pulmonary disease (13.9 %), diabetes (8.0 %), hypothyroidism (6.3 %) and malignancy (5.0 %). After 5 years, 41.0 % had developed at least one new co-morbidity, the most common being: hypertension (15.1 %), malignancy (7.6 %), stroke/transient ischemic accident (5.1 %), myocardial infarction (4.3 %) and osteoporosis (3.7 %). Age at disease onset, a raised erythrocyte sedimentation rate (ESR) at inclusion, previous treatment with glucocorticoids (GC; p < 0.001 for all), extra-articular RA (Ex-RA; p < 0.01), DAS28 (area under the curve) at 24 months (p < 0.05), previous smoking at inclusion (p = 0.058) and male gender (p < 0.01) were associated with a new co-morbidity overall at T5. Treatment with biologics (p < 0.05) reduced the risk. In multiple logistic regression modelling, ESR (p = 0.036) at inclusion was associated with a new co-morbidity after 5 years, adjusted for age, sex, smoking and GC treatment. In a similar model, Ex-RA (p < 0.05) was associated with a new co-morbidity at T5. In a third model, adjusted for age and sex, a new pulmonary co-morbidity was associated with a smoking history at inclusion (p < 0.01), but not with ESR. Conclusion: There was substantial co-morbidity among early RA patients already at disease onset, with considerable new co-morbidity being added during the first five years. Measures of disease activity were associated with the occurrence of a new co-morbidity indicating that the inflammation is of importance in this context.

  • 173.
    Isaksson, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Screening and simple counselling affect traditional cardiovascular risk factors in patients with early rheumatoid arthritis2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no Suppl. 127 Meeting Abstract PP234, p. 76-76Article in journal (Other academic)
    Abstract [en]

    Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) and increased mortality in CVD. The cause of this increase has not been completely established, but chronic inflammation is thought to play a role. Traditional cardiovascular risk factors also appear to be important and may be potentiated by this inflammation. The Swedish Society for Rheumatology (SRF) has developed a set of guidelines for screening and primary prevention of CVD in patients with RA. The aim of this study was to evaluate these guidelines in a clinical setting.

    Method: Forty-seven patients newly diagnosed with RA during 2012 at the Department of Rheumatology, University Hospital of Umeå were recruited. Three months after initial diagnosis of RA, patients were examined physically and blood samples were collected with regard to traditional cardiovascular risk factors according to the guidelines from the SRF. Tests of cardiorespiratory fitness were also performed. Additionally, patients received simple counselling regarding matters of diet, tobacco use and exercise from a nurse and a physiotherapist, respectively. The counselling session, based upon national guidelines from the National Food Agency and the Public Health Agency, was performed once per patient and lasted for approximately 45 minutes. A follow-up was performed 9 months after the first examination. This intervention was integrated into the clinic’s pre-existing early RA follow-up programme. The results were adjusted for disease activity and disability.

    Results: Among the 47 included patients, 45 reached the 9-month follow-up. Two were excluded because of delayed follow-up. Mean diastolic blood pressure decreased significantly from 80 to 77 mmHg (p < 0.05). Mean S-cholesterol decreased significantly from 5.5 to 5.2 mmol/L (p < 0.05). Mean ApoA1/ApoB decreased significantly from 0.73 to 0.65 (p < 0.05). In all the remaining variables (waist circumference, BMI, systolic blood pressure, LDL, HDL, triglycerides, FP-glucose), a clear decreasing trend could be observed (p > 0.05). Aerobic capacity according to Åstrand remained unchanged (p > 0.05).

    Conclusions: Several traditional risk factors for CVD were improved at the 9-month follow-up. This suggests that this model of screening according to the SRF guidelines and simple counselling according to national guidelines might be useful in primary prevention of CVD in patients with RA.

  • 174. Jiang, X
    et al.
    Kallberg, H
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Klareskog, L
    Alfredsson, L
    Padyukov, L
    A dense mapping of HLA region for study of interaction with smoking in the development of rheumatoid arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no Suppl. 3, p. 67-67Article in journal (Refereed)
  • 175. Jiang, Xia
    et al.
    Kallberg, Henrik
    Chen, Zuomei
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Davila, Sonia
    Klareskog, Lars
    Padyukov, Leonid
    Alfredsson, Lars
    An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis2016In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, no 1, p. 149-155Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 176. Jiang, Xia
    et al.
    Kallberg, Henrik
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Klareskog, Lars
    Padyukov, Leonid
    Alfredsson, Lars
    A Dense Mapping Of Human Leukocyte Antigen Region For Study Of Interaction With Smoking In The Development Of Rheumatoid Arthritis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, p. S799-S799, Meeting Abstract: 1875Article in journal (Other academic)
  • 177. Jiang, Xia
    et al.
    Sundström, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Alfredsson, Lars
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Bengtsson, Camilla
    High sodium chloride consumption enhances the effects of smoking but does not interact with SGK1 polymorphisms in the development of ACPA-positive status in patients with RA2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, no 5, p. 943-945Article in journal (Refereed)
  • 178. Jiang, Xia
    et al.
    Sundström, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Alfredsson, Lars
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Bengtsson, Camilla
    Sodium Chloride Consumption, Together with Smoking, Is Associated with ACPA Positivity2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, article id 2018Article in journal (Other academic)
  • 179.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Insights into the processes preceding the onset of rheumatoid arthritis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by the production of anti-citrullinated protein antibodies (ACPA) in the majority of all patients and a persistent inflammation in the synovial tissue leading to joint destruction. The aetiology of RA remains to a large extent unknown but is believed to be a complex interplay between genetic, environmental and stochastic factors. Recently, several infectious agents have been shown to have the capacity to induce citrullination of both endogenous and exogenous antigens e.g., Epstein-Barr virus (EBV) and Porphyromonas gingivalis (P.gingivalis). Disease progression in patients with RA is suggested to be a longstanding process that begins several years before symptom onset of RA. This hypothesis is supported by studies showing increased antibody levels against ACPA and disease related cytokines/chemokines several years before symptom onset of RA. The presence of ACPA is highly specific for RA and is already used as an indicator of progression and prognosis of the disease. This thesis is aimed to further investigate the origin and role of ACPA and the processes preceding the development of RA. New insights into these processes are of importance in order to be able to prevent the disease onset, achieve better diagnostic methods and treatments in the future.

    All of the individuals included in these papers, had attended to the Department of Rheumatology at Umeå University to receive their diagnosis of RA. The register of the patients were thereafter co-analysed with the register of the Medical Biobank of Northern Sweden. Plasma/sera samples were analysed for antibodies and receptor activator of nuclear factor kappa-B ligand (RANKL) using different ELISA techniques from individuals before symptom onset (pre-symptomatic individuals) and at disease onset (patients). Cytokines/chemokines were analysed using Meso Scale Discovery methods. Levels of marginal jawbone loss were measured using dental radiographs from premolar/molar regions. The Larsen score at disease onset was used to grade radiographs of hands and feet.

    In Paper I antibodies against Epstein-Barr virus nuclear antigen (EBNA) 1 and 2 (VCP1 and VCP2) and histone 4 (H4) derived citrullinated peptides (HCP1 and HCP2) were found to predate symptom onset of RA. In Paper II, antibodies against anti-P.gingivalis (anti-CPP3 and -RgpB IgG) were significantly increased in pre-symptomatic individuals and were detectable several years before symptom onset of RA. In Paper III the concentration of RANKL was shown to be increased several years before symptom onset of RA, especially in ACPA/rheumatoid factor (RF)/anti-carbamylated (CarP) antibody positive individuals. Positivity for RANKL was found to appear later in time than both positivity for ACPA, RF and anti-CarP antibodies. The highest Larsen score at disease onset was yielded when combining positivity for RANKL and anti-CarPivantibodies. In Paper IV periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals who never smoked, compared with matched controls. RANKL positive individuals particularly those that were also ACPA positive, had a significantly greater extent of jawbone loss in comparison to those individuals who were RANKL negative.

    Antibodies against citrullinated exogenous and endogenous peptides were found to be associated with the symptom onset of RA. No hierarchy among the citrullinated epitopes could be identified. RANKL levels were particular increased in ACPA-positive individuals, and RANKL positivity appeared later in time than the general ACPA response. Periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals, who never smoked.

  • 180.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Pratesi, Federico
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    D'Amato, Claudia
    Bartaloni, Debora
    Migliorini, Paola
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 127Article in journal (Refereed)
    Abstract [en]

    Background: Anti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens. Methods: A cohort of 521 individuals sampled before symptoms of RA appeared and 272 population controls were identified from the Biobank of Northern Sweden; 241 samples from patients with early RA were also collected. ACPA were detected by ELISA on viral citrullinated peptides (VCP) derived from Epstein-Barr-virus nuclear antigen (EBNA) 1 and EBNA2 (VCP1 and VCP2) and histone-4-derived citrullinated peptides (HCP1 and HCP2). Results: In pre-symptomatic individuals vs. patients with early RA, anti-VCP1 antibodies were detected in 10.4 % vs. 36.1 %, anti-VCP2 in 17.1 % vs. 52.3 %, anti-HCP1 in 10.2 % vs. 37.3 %, and anti-HCP2 in 16.3 % vs. 48.5 %, respectively. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals vs. controls (p < 0.001) and were increased approaching symptom onset. Anti-VCP and anti-HCP appeared simultaneously (median (IQR) 5.3 (6) years before symptom onset) and in combination yielded a high-risk ratio for disease development (OR = 8.0-18.9). Anti-VCP2 and anti-HCP2 antibodies were associated with HLA-DRB1*0401 in pre-symptomatic individuals. Three peptidylarginine deiminase (PAD)I3/PADI4 single nucleotide polymorphisms (SNPs) were significantly associated with anti-HCP1. Conclusions: Anti-VCP and anti-HCP antibodies pre-date symptom onset and predict disease development, but no hierarchy of citrullinated epitopes can be identified. These results suggest that no inciting citrullinated antigen so far described is common to all patients with RA. The association between PADI3/PADI4 polymorphism and anti-HCP1 antibodies suggests a novel link between deimination and production of ACPA.

  • 181.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sherina, Natalia
    Kharlamova, Nastya
    Larsson, Barbro
    Israelsson, Lena
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lundberg, Karin
    Plasma Concentrations of Antibodies to Porphyromonas Gingivalis Are Increased before Onset of Symptom of Rheumatoid Arthritis2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, article id 524Article in journal (Other academic)
  • 182.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Sherina, Natalia
    Kharlamova, Nastya
    Potempa, Barbara
    Larsson, Barbro
    Israelsson, Lena
    Potempa, Jan
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lundberg, Karin
    Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 201Article in journal (Refereed)
    Abstract [en]

    Background: The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production. Methods: A case-control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA. Results: Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean +/- SEM; 152.7 +/- 14.8 AU/ml) and in RA patients (114.4 +/- 16.9 AU/ml), compared with controls (p < 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 +/- 0.59 and 9.29 +/- 1.81 AU/ml, respectively) compared with controls (p < 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis. Conclusions: Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.

  • 183.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis2017In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56, no 12, p. 2190-2196Article in journal (Refereed)
    Abstract [en]

    Objectives: RANK ligand (RANKL) is involved in destruction and osteoporosis in RA. In this study, the relationships between RANKL and ACPA, anti-carbamylated protein antibodies (anti-CarP), cytokines and chemokines were analysed in individuals before the onset of RA symptoms, and their associations with radiological findings at disease onset were assessed.

    Methods: This was a case-control study performed within the Medical Biobank of Northern Sweden that included 470 pre-symptomatic individuals [334 women and 136 men; mean (S.D.) age 52.3 (9.4) years] using blood samples donated before symptom onset (pre-dating time; 5.0 years) and 96 controls (60 women and 36 men). Plasma was analysed for RANKL (BioVendor, Karasek, Brno, Czech Republic), anti-CCP2 antibodies (Eurodiagnostics, Malmo, Sweden), anti-CarP antibodies (in-house ELISA), ACPA specificities (ISAC-platform, Phadia AB, Uppsala, Sweden) and cytokines/chemokines (Meso Scale Discovery methods, Rockville, MD, USA). Radiographs of hands and feet were graded using the Larsen score.

    Results: The concentration of RANKL was higher in the pre-symptomatic individuals compared with controls; mean (S.E.M.): 0.50 (0.03) vs 0.22 (0.02) nmol/l (P < 0.001). The concentration increased gradually over time until symptom onset but appeared later than ACPA/RF/anti-CarP antibodies. Positivity for these antibodies yielded higher levels of RANKL compared with seronegativity (P < 0.001). RANKL concentrations were significantly associated with IL-6 and IL-10 concentrations. The combination of positivity for RANKL and anti-CarP antibodies resulted in a higher Larsen score at diagnosis beta = 6.18 (95% CI: 0.93, 11.43; P = 0.022).

    Conclusion: RANKL concentrations were increased several years before symptom onset for RA, particularly in ACPA/RF/anti-CarP-positive individuals, all detectable earlier than RANKL. Positivity for RANKL and anti-CarP antibodies yielded the highest Larsen score at disease onset.

  • 184.
    Johansson, Martin
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Systemic lupus erythematosus and rheumatoid arthritis: analyses of candidate genes involved in immune functions, for susceptibility and severity2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with systemic manifestations characterized by auto-antibodies directed against different parts of the cell nucleus including DNA, histones and ribosomes. The systemic inflammation can cause damage to multiple organs, e.g., kidneys, skin, heart, lungs and the nervous system. Rheumatoid arthritis (RA) is another autoimmune rheumatic disease characterized by auto-antibodies, mainly directed against the Fc-part of immunoglobulin G (rheumatoid factor (RF)) but also against citrullinated peptides/proteins (ACPAs). The inflammation in RA primarily involves the joints resulting in inflamed synovial tissue and destruction of cartilage. The aetiology of both SLE and RA is unclear but there is a genetic contribution predominantly of genes involved in inflammation. The diseases are believed to be multifactorial, or complex, meaning that multiple genes interact with environmental, infectious and hormonal factors, thus increasing the risk of developing disease.

    The aim of this study was to investigate different candidate genes involved in functions of the immune system and their relationship with SLE and RA susceptibility and severity.

    The patients and controls were from the four northernmost counties of Sweden, which is a fairly homogenous population well suited for genetic studies. Two single nucleotide polymorphisms (SNPs) in the oestrogen receptor α (ESR1) gene were analysed in SLE. No association was found between the SNPs and SLE per se however the minor alleles (PvuII C and XbaI G) were associated with skin manifestations and later disease onset, thus representing a milder form of the disease. A SNP in the programmed cell-death 1 (PDCD1) gene, which codes for PD-1, an inhibitory molecule involved in T-cell activation, was studied. No association was seen between the risk allele (PD-1.3A) and SLE susceptibility but a strong association was found with renal disease. A risk allele of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene that codes for a protein called Lyp which acts as a negative regulator of T-cell receptor (TCR) signalling was significantly associated with SLE in three different case-control sets across Sweden. Both PDCD1 and PTPN22 were independently associated with renal disease. The PTPN22 gene has been associated with numerous autoimmune diseases and was evaluated in another auto-antibody producing disease, RA. From the Medical Biobank of northern Sweden samples donated before the development of symptoms of RA were identified. In these individuals, who subsequently developed RA, the 1858T risk allele in combination with ACPAs gave a high relative risk (>132) for developing RA. The association between PTPN22 and RA was confirmed in a larger material of patients with early RA. The 1858T allele, of the three SNPs investigated, was shown to be the true risk allele associated with auto-antibody positive RA. A functional role of PTPN22 in TCR-mediated activation of T cells from patients with SLE and RA was not demonstrated.

    In conclusion, minor alleles of two SNPs in the ESR1 gene were associated with a milder form of SLE. The risk allele in the PDCD1 gene was associated with renal disorder in SLE. The risk allele 1858T of the PTPN22 gene was associated with SLE, particularly with renal disease. The 1858T allele in combination with auto-antibodies was a risk factor for developing RA. In early diagnosed RA, the 1858T allele was highly associated with RA and in particular with auto-antibody positive RA.

  • 185.
    Johansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Evaluation of three different polymorphisms of PTPN22 in rheumatoid arthritisManuscript (preprint) (Other academic)
    Abstract [en]

    Objectives To compare the associations of three SNPs (rs3811021, rs2476601 (1858C/T) and rs2488457 (-1123G/C)) of the PTPN22 gene: in patients with RA and to analyse functional properties of the 1858T allele.

    Methods A total of 769 consecutively included patients with early RA and 1054 population-based matched controls were genotyped for the rs3811021, rs2476601, and rs2488457 polymorphisms using a TaqMan instrument.  T-lymphocytes from RA patients, SLE patients and controls, heterozygous for the +1858T allele were compared with cells homozygous for +1858C. The T-cells were cultivated in the presence or absence of either PMA/Ionomycine or antibodies to CD3ε and CD28. Cell activation was quantified by measuring levels of interleukin-2 produced using an ELISA.

    Results The -1123C and 1858T alleles were associated with RA (OR=1.35(1.14-1.60), p=0.0004 and OR=1.65(1.35-2.01), p=3x10-6, respectively). These associations, together with a haplotype containing both risk alleles, retained statistical significance after conducting a permutation test. The SNPs -1123G/C and 1858C/T were in strong linkage disequilibrium (LD), however, the 1858T allele was mainly associated with HLA-SE, IgM-RF or ACPA positive RA whereas the -1123C allele was associated regardless of any stratification of the patient group. Patients having both -1123C and 1858T had significantly higher frequency of HLA-SE (OR=2.03(1.29-3.19)) and ACPA (OR=2.21(1.38-3.53)) compared with patients having -1123C but not 1858T. In the functional study, the 1858T allele was not shown to increase the negative regulation of T-lymphocyte activation compared with 1858C in either patients or controls.

    Conclusions The true association with RA was seen with the 1858T allele. The -1123C allele was only associated with RA through being in LD with the 1858T allele. The 1858T allele was associated with HLA-SE positive and ACPA positive RA whereas the -1123C allele was associated regardless of stratification.  The proposed function of the 1858T allele could not be shown using this experimental protocol.

  • 186.
    Johansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 1, p. R19-Article in journal (Refereed)
  • 187.
    Johansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 6, p. 1665-1669Article in journal (Refereed)
  • 188. Jonsen, Andreas
    et al.
    Bengtsson, Anders A.
    Bengtsson, Christine
    Gunnarsson, Iva
    Gustafsson, Johanna
    Hjalte, Frida
    Leonard, Dag
    Pettersson, Susanne
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ronnblom, Lars
    Sjowall, Christopher
    Carlsson, Katarina Steen
    Svenungsson, Elisabet
    Willim, Minna
    Nived, Ola
    Direct and Indirect Costs For Patients With Systemic Lupus Erythematosus In National Cohorts In Sweden2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, p. S752-S752, Meeting Abstract: 1769Article in journal (Other academic)
  • 189. Jonsen, Andreas
    et al.
    Hjalte, Frida
    Willim, Minna
    Carlsson, Katarina Steen
    Sjowall, Christopher
    Svenungsson, Elisabet
    Leonard, Dag
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Pettersson, Susanne
    Gunnarsson, Iva
    Zickert, Agneta
    Gustafsson, Johanna T.
    Ronnblom, Lars
    Petersson, Ingemar F.
    Bengtsson, Anders A.
    Nived, Ola
    Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts2016In: Seminars in Arthritis & Rheumatism, ISSN 0049-0172, E-ISSN 1532-866X, Vol. 45, no 6, p. 684-690Article, review/survey (Refereed)
    Abstract [en]

    Objectives: The main objectives of this study were to calculate total costs of illness and cost -driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden. Methods: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency. Results: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941(sic)), of which direct cost was 63,672kr ($10,188 = 7004(sic)) and the indirect cost was 144,883 SEK ($23,181 = 15,937(sic)), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs. Conclusion: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (= 129.5 million (sic)). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs. (C) 2016 Elsevier Inc. All rights reserved.

  • 190.
    Jonsson, E.
    et al.
    Dept Rheumatol, Östersund, Sweden.
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Inst Publ Hlth & Clin Med, Östersund, Sweden.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Quality of life in SLE of various disease durations and in correlation to disease burden: a cross sectional study2015In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 33, no 3 Supplement: 90, p. S40-S40, article id Meeting Abstract: P5.09Article in journal (Other academic)
  • 191.
    Juneblad, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Psoriatic arthritis: a complex disease: analyses on genetic and serological biomarkers and of comorbidity2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Psoriatic Arthritis (PsA) is a heterogonous inflammatory arthritis associated with psoriasis. The disease leads to inflammation of peripheral joints, axial skeleton and/or enthesites, and can result in severe destruction of affected joints. In contrast to rheumatoid arthritis (RA), most individuals with PsA are seronegative for rheumatoid factor (RF) and/or anti-citrullinated protein/peptide antibodies (ACPA) and the distal interphalangeal (DIP) joints are often involved. Dactylitis, a diffuse swelling of an entire digit (finger or toe), is also common. Traditional markers of systemic inflammation, such as erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) are elevated in only 50% of the individuals with PsA.

    Underlying genetic factors are considered important for the aetiology, disease expression and prognosis of PsA. To date no specific biomarker for PsA disease or disease activity/severity is available and there is a need for diagnostic and prognostic tools to meet the challenge of early diagnosis and assessment of disease severity.

    An increased risk of co-morbidity, particularly cardiovascular disease (CVD), has been demonstrated in patients suffering from different rheumatic diseases, e.g. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Corresponding data for patients with PsA are more limited, but evidence exists for an increased risk of mortality and cardiovascular morbidity. However, published results are conflicting and heterogeneity among studies makes interpretation of data difficult.

    The aim of this study was to investigate genetic and serological biomarkers, and also mortality and cardiovascular comorbidity, in different phenotypes of PsA and in comparison with healthy controls. Patients with PsA were included between 1995 and 2015, the majority from the county of Västerbotten, except for two cohorts from Örnsköldsvik (n=55) and Östersund (n=98).

    The genetic polymorphism PTPN22+1858C/T, previously found to be associated with several autoimmune diseases, was also found associated with PsA, the results were later confirmed in a genome wide association study (GWAS). Additionally, among PsA patients, the minor allele, T, was associated with the number of deformed joints and dactylitis (Paper I). 

    Genetic polymorphisms in genes related to the inflammasome were also investigated, both in comparison with healthy controls and in relation to different phenotypes of PsA (Paper II). An association was identified between patients with PsA and the polymorphism CARD8-C10X in comparison with controls. In addition, associations between various inflammasome polymorphisms and different clinical phenotypes of PsA were detected.

    To investigate the relation of serological biomarkers and PsA, individuals with blood samples collected in conjunction with clinical investigation were selected (Paper III).  Associations with different biomarkers and different clinical phenotypes of PsA were identified In addition, associations were found with different biomarkers and patients with moderate/high disease activity at clinical investigation, confirming the inflammatory nature of the disease.

    Mortality and incidence of acute cardiovascular disease were investigated with standardized mortality rateratio (SMR) and standardized incidence ratio (SIR) compared with the general population of Västerbotten (Paper IV). An increased SMR for diseases of the circulatory system in PsA compared with controls was found. Among PsA patients, death was associated with a composite disease activity index (DAI) and with a disease phenotype including both axial- and peripheral joint involvement. 

    In conclusion, associations were found with different clinical phenotypes of PsA, both with genetic polymorphisms and serological biomarkers that confirm the inflammatory nature of the disease and illustrate the disease heterogeneity. As in many other inflammatory diseases, an increased cardiovascular mortality was found that highlights the importance of considering cardiovascular risk factors in patients with PsA.

  • 192.
    Juneblad, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mortality and cardiovascular comorbidity in psoriatic arthritis2014In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 32, no 5, p. 796-796Article in journal (Other academic)
  • 193.
    Juneblad, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapaa-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Disease activity and increased risk of cardiovascular death among patients with psoriatic arthritis2016In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 45, no Suppl. 128, p. 29-29, article id PP33Article in journal (Refereed)
  • 194.
    Juneblad, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Association between inflammasome-related polymorphisms and psoriatic arthritisManuscript (preprint) (Other academic)
  • 195.
    Juneblad, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Association between the PTPN22 +1858 C/T polymorphism and psoriatic arthritis2011In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, article id R45Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The purpose of the present study was to investigate the frequency of the PTPN22 +1858 C/T single nucleotide polymorphism (SNP) (rs 2476601), previously shown to be associated with several autoimmune diseases, in patients with psoriatic arthritis (PsA) in comparison with population based controls.

    METHODS: A total of 291 patients (145 male/146 female, mean age (± S.D.) 52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601 (PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls.

    RESULTS: Carriage of the risk allele, PTPN22+1858T, showed a significant association with patients with PsA compared with controls (χ2 = 6.56, P = 0.010, odds ratio (OR) 1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) (5.9 ± 1.2 vs 2.8 ± 0.5; P = 0.005).

    CONCLUSIONS: In this study the +1858T allele of the PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.

  • 196.
    Juneblad, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Disease activity and increased risk of cardiovascular death among patients with psoriatic arthritis2016In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 43, no 12, p. 2155-2161Article in journal (Refereed)
    Abstract [en]

    Objective: Recent studies indicate increased cardiovascular (CV) morbidity and mortality in patients with psoriatic arthritis (PsA), but results are inconsistent. This prompted our investigation of the mortality rate, cause of death, and incidence of acute CV events in patients from northern Sweden with PsA.

    Methods: Patients with established PsA (464) were included. To calculate standardized mortality ratio (SMR) and standardized incidence ratio (SIR) for CV events, data were extracted from the National Causes of Death Register and the National Inpatient Care Register in Sweden, and compared with the general population. The study period was 1995-2011. To study the effect of inflammatory activity, a composite disease activity index (DAI) was used.

    Results: The SMR (95% CI) for overall mortality and diseases of the circulatory system (International Classification of Diseases, 10th edition; I00-I99) was 1.22 (0.89-1.63) and 1.64 (1.02-2.52), respectively. In regression analysis, DAI was significantly associated with death (OR 1.99, 95% CI 1.41-2.80) when adjusted for age and sex (p < 0.001), and remained significant after stratifying patients into the 2 major causes of death: diseases of the circulatory system and malignant neoplasms. Peripheral and axial disease was associated with death (OR 4.02, 95% CI 1.84-8.84, p < 0.001) compared with peripheral disease only. The SIR (95% CI) for a CV event (myocardial infarction or stroke) was 0.597 (0.40-0.86); this association was only significant in men.

    Conclusion: Patients with PsA had a small but significant increase in SMR for death due to diseases of the circulatory system compared with the general population. Among patients, death was associated with DAI, as well as axial involvement in combination with peripheral disease, indicating more aggressive disease phenotypes.

  • 197.
    Juneblad, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Expression of biomarkers in relation to disease manifestations of psoriatic arthritisManuscript (preprint) (Other academic)
  • 198.
    Karlsson, Berit
    et al.
    Department of Rheumatology, University Hospital, Umeå, Sweden.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Life satisfaction in early rheumatoid arthritis: a prospective study.2006In: Scand J Occup Ther, ISSN 1103-8128, Vol. 13, no 3, p. 193-9Article in journal (Refereed)
  • 199. Kastbom, Alf
    et al.
    Coster, Lars
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Chatzidionysiou, Aikaterini
    van Vollenhoven, Ronald F.
    Padyukov, Leonid
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Saevarsdottir, Saedis
    Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 5, p. e001524-Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine whether a polymorphism in the Fc gamma receptor type IIIA (FCGR3A-F158V), influencing immunoglobulin G binding affinity, relates to the therapeutic efficacy of rituximab in rheumatoid arthritis (RA) patients. Design: Observational cohort study. Setting: Three university hospital rheumatology units in Sweden. Participants: Patients with established RA (n=177; 145 females and 32 males) who started rituximab (Mabthera) as part of routine care. Primary outcome measures: Response to rituximab therapy in relation to FCGR3A genotype, including stratification for sex. Results: The frequency of responders differed significantly across FCGR3A genotypes (p=0.017 in a 3x2 contingency table). Heterozygous patients showed the highest response rate at 83%, as compared with patients carrying 158FF (68%) or 158VV (56%) (p=0.028 and 0.016, respectively). Among 158VV patients, response rates differed between male and female patients (p=0.036), but not among 158FF or 158VF patients (p=0.72 and 0.46, respectively). Conclusions: Therapeutic efficacy of rituximab in RA patients is influenced by FCGR3A genotype, with the highest response rates found among heterozygous patients. This may suggest that different rituximab mechanisms of action in RA are optimally balanced in FCGR3A-158VF patients. Similar to the previously described associations with RA susceptibility and disease course, the impact of 158VV on rituximab response may be influenced by sex.

  • 200. Kastbom, Alf
    et al.
    Johansson, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Verma, Deepti
    Söderkvist, Peter
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    CARD8 p.C10X polymorphism is associated with infl ammatory activity in early rheumatoid arthritis2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 4, p. 723-726Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: CARD8 and NLRP3 are constituents of the inflammasome, which regulates interleukin 1beta production. We evaluated the influence of polymorphisms in CARD8 and NLRP3 on rheumatoid arthritis (RA) susceptibility and severity. METHODS: CARD8 p.C10X and NLRP3 p.Q705K genotypes were assessed in >500 controls and early RA patients from northern Sweden. The patients were monitored regularly during 2 years. The 28 joint disease activity score (DAS28) and its separate components were compared across genotypes. RESULTS: Patients with >/=1 variant allele in CARD8 (CARD8-X) had increased DAS28, tender joint count and erythrocyte sedimentation rate during the 2 year follow-up, despite receiving disease-modifying anti-rheumatic drugs to a higher extent. CARD8-X was significantly overrepresented among patients who received anti-TNF therapy during the first two years. CARD8 and NLRP3 genotypes did not influence radiological joint damage or associate with an increased susceptibility. CONCLUSIONS: Carriage of CARD8-X associates with a worse disease course in early RA.

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