| 1. |
- Delcoigne, Bénédicte, et al.
(author)
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How does current disease activity in rheumatoid arthritis affect the short-term risk of acute coronary syndrome? : A clinical register based study from Sweden and Norway
- 2023
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In: European journal of internal medicine. - 0953-6205 .- 1879-0828. ; 115, s. 55-61
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Journal article (peer-reviewed)abstract
- Objectives: To estimate short-term risks of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) as a function of current RA disease activity including remission.Methods: Data from clinical visits of RA patients in Sweden (SE) and Norway (NO) between January 1st 2012 until December 31st 2020 were used. At each visit, patient's disease activity was assessed including remission status (measured with several metrics). Through linkage to national health and death registers, patients were followed up for incident ACS up to six months from each visit. We compared the short-term risk of ACS in patients not in remission vs. in remission using Cox regression analyses with robust standard errors, adjusted for country and covariates (e.g., age, sex, prednisolone use, comorbidities). We also explored disease activity categories as exposure.Results: We included 212,493 visits (10,444 from Norway and 202,049 from Sweden) among 41,250 patients (72% women, mean age at visit 62 years). During the 6-month follow-ups, we observed 524 incident ACS events. Compared to patients in remission, patients currently not in remission had an increased rate of ACS: adjusted hazard ratio (95% confidence interval) 1.52 (1.24–1.85) with DAS28 metric. The crude absolute six-month risks were 0.2% for patients in remission vs. 0.4% for patients with DAS28 high disease activity. The use of alternative RA disease activity and remission metrics provided similar results.Conclusion: Failure to reach remission is associated with elevated short-term risks of ACS, underscoring the need for CV risk factor optimization in these patients.
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| 2. |
- Delcoigne, B., et al.
(author)
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SHORT- AND LONGER-TERM RISKS FOR ACUTE CORONARY SYNDROME IN PATIENTS WITH RHEUMATOID ARTHRITIS STARTING TREATMENT WITH DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS : A COLLABORATIVE OBSERVATIONAL HEAD-TO-HEAD STUDY ACROSS FIVE NORDIC RHEUMATOLOGY REGISTERS
- 2021
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80, s. 63-64
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Journal article (other academic/artistic)abstract
- Rheumatoid Arthritis (RA) is associated with increased cardiovascular co-morbidity including acute coronary syndrome (ACS), partly due to effects of systemic inflammation. Disease-modifying anti-rheumatic drugs (DMARDs) may reduce RA disease activity, but act through several pathways and may themselves have an impact on cardiovascular risks. Whether the risks of ACS associated with biologic (b) and targeted synthetic (ts) DMARDs differ is still unknown.Objectives:To assess and compare incidences of ACS during treatment of RA with etanercept (ETA), adalimumab (ADA), infliximab (INF), certolizumab pegol (CTZ), golimumab (GOL), rituximab (RIT), abatacept (ABA), tocilizumab (TCZ), baricitinib (BAR) or tofacitinib (TOF).Methods:We defined and pooled treatment cohorts of patients starting any of the above treatments between 2008 and 2017 from clinical rheumatology registers in Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). One patient could contribute several treatment episodes. Age, sex, co-medication (methotrexate, prednisolone), number of previous b/tsDMARDs, CRP, comorbidities (cardiovascular (including ACS (defined as ICD-10: I20.0, I21.0-4, I21.9) and cerebrovascular disease, thromboembolic events, diabetes, hospitalized infection, cancer, kidney failure, COPD) and associated drugs were extracted and used as adjustment in Cox regression analyses comparing the incidence of ACS between treatments. We used several follow-up lengths (1, 2, and up to 5 years) and two different risk windows (ACS on drug [ending follow-up on treatment discontinuation] and ACS ever since treatment start [disregarding any treatment discontinuation]). We also stratified by age and number of previous b/tsDMARDs.Results:We included 40850 treatment courses in 24083 patients (DK 7271, FI 3732, NO 1540, and SE 11540; around 75% women). ETA was the most common treatment (27%) whereas BAR and TOF comprised <1%, and the other DMARDs 6-14% each. The proportions with a history of ACS at treatment start ranged from 1.2% (NO) to 1.8% (DK).We found 780 incident ACS events during 141 326 person-years (pyrs) in the 5-year follow-up time and “ACS ever since treatment start” risk window, resulting in a crude incidence rate of 5.5 events per 1000 pyrs. No event was recorded for BAR nor TOF, which also had the shortest follow-up. Adjusted hazard ratios (HR) increased slightly with longer follow-up times, but the two risk windows provided similar HRs. For the 5-year follow-up, RIT was associated with an increased risk of ACS compared to ETA (Table), while no association was observed for shorter follow-up times. Stratifying on age did not modify the associations. Separate analyses by number of previous b/tsDMARDs suggested that ABA (HR=1.8, 95% CI 1.0-3.3), INF (HR=2.2, 95% CI 1.0-4.6) and RIT (HR=1.9, 95% CI 1.1-3.4) were associated with increased risks of ACS compared to ETA in the subgroup of patients with two or more previous bDMARDs (Figure), whereas no differences were found among patients starting either drug as 1st/2nd bDMARD.Table 1.Comparisons of risks for ACS during a 5-year follow-up since start of bDMARD treatment.DrugN eventspyrsCrude incidence rate/ 1000 pyrsHR (95% CI)1ETA175359174.9ref.ADA115240934.81.0 (0.8-1.3)CTZ54141583.80.9 (0.6-1.2)GOL4090064.41.1 (0.8-1.5)INF106178036.01.2 (0.9-1.5)ABA70107956.51.1 (0.8-1.4)RIT158166229.51.3 (1.0-1.6)TCZ62128664.80.9 (0.5-1.2)BAR036TOF030Pyrs: person-years; HR: hazards ratio1 adjustment: see text.Conclusion:In this cohort including ≥ 24,000 patients followed for up to 5 years, the ACS incidence rate was 5.5/1000 pyrs, with RIT showing an increased risk compared to ETA. In clinical practice, the choice of bDMARD does not seem to influence ACS risk in the short term. In the longer term, differences in ACS risk between bDMARDs may reflect channeling to these, or truly differential effects in subpopulations of patients.Acknowledgements:Partly funded by Nordforsk and ForeumDisclosure of Interests:Bénédicte Delcoigne: None declared, Lotta Ljung: None declared, Sella Aa. Provan Speakers bureau: Novartis, Consultant of: Novartis, Grant/research support from: Boehringer- Ingelheim, Bente Glintborg Grant/research support from: Pfizer, BMS, AbbVie, Kathrine Lederballe Gron Grant/research support from: BMS, Merete L. Hetland Consultant of: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Grant/research support from: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Niels Steen Krogh: None declared, Nina Trokovic: None declared, Heikki Relas Speakers bureau: Abbvie, Celgene, Pfizer, Grant/research support from: Abbvie, Celgene, Pfizer, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Brigitte Michelsen Consultant of: Novartis (paid to employer), Grant/research support from: Novartis (paid to employer), Johan Askling Consultant of: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. These entities have entered into agreements with Karolinska Institutet with JA as principal investigator, mainly in the context of safety monitoring of biologics via the ARTIS national safety monitoring system.
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| 3. |
- Delcoigne, Benedicte, et al.
(author)
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Short-term, intermediate-term and long-term risks of acute coronary syndrome in cohorts of patients with RA starting biologic DMARDs : Results from four Nordic countries
- 2022
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:6, s. 789-797
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Journal article (peer-reviewed)abstract
- Objectives: To compare the 1-year, 2-year and 5-year incidences of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) starting any of the biologic disease-modifying antirheumatic drugs (bDMARDs) currently available in clinical practice and to anchor these results with a general population comparator.Methods: Observational cohort study, with patients from Denmark, Finland, Norway and Sweden starting a bDMARD during 2008-2017. Time to first ACS was identified through register linkages. We calculated the 1-year, 2-year and 5-year incidence rates (IR) (on drug and ever since treatment start) and used Cox regression (HRs) to compare ACS incidences across treatments taking ACS risk factors into account. Analyses were further performed separately in subgroups defined by age, number of previous bDMARDs and history of cardiovascular disease. We also compared ACS incidences to an individually matched general population cohort.Results: 24 083 patients (75% women, mean age 56 years) contributing 40 850 treatment courses were included. During the maximum (5 years) follow-up (141 257 person-years (pyrs)), 780 ACS events occurred (crude IR 5.5 per 1000 pyrs). Overall, the incidence of ACS in RA was 80% higher than that in the general population. For all bDMARDs and follow-up definitions, HRs were close to 1 (etanercept as reference) with the exception of the 5-year risk window, where signals for abatacept, infliximab and rituximab were noted.Conclusion: The rate of ACS among patients with RA initiating bDMARDs remains elevated compared with the general population. As used in routine care, the short-term, intermediate-term and longer-term risks of ACS vary little across individual bDMARDs.
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| 4. |
- Delcoigne, Benedicte, et al.
(author)
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The influence of patient demographics on disease activity measurments in theumatoid arthritis
- 2019
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78, s. 1423-1424
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Journal article (other academic/artistic)abstract
- Background: Several indexes have been constructed for the measurement of disease activity in rheumatoid arthritis (RA) patients, including the Disease Activity Score 28-joint count, which either includes the Erythrocyte Sedimentation Rate (DAS28ESR) or the C-reactive protein concentration (DAS28CRP), and the Clinical Disease Activity Index (CDAI). The categorization of the results of these three indexes into levels of disease activity (Remission, Low, Moderate and High) is used to assess patient outcomes, and to guide medical decisions regarding treatment. However, the different indexes can lead to somewhat different classification, and hence influence treatment decisions.1 Objectives: To investigate how DAS28ESR, DAS28CRP and CDAI indexes are associated to age and sex in RA patients. To investigate the agreement between indexes and between categories of disease activity levels.Methods: We identified a cohort of RA patients, registered in the Swedish Rheumatology Quality Register between January 1st2014 and December 31st2017. The indexes were obtained from the first visit at the time point of RA diagnosis, and at the visit registered at the start of a first ever biological treatment prescription. Linear models were used to investigate the correlation between the indexes, age and sex. The agreement between the indexes was explored with Bland-Altman plots. The agreement between disease activity levels was evaluated through kappa statistics.Results: Data were analyzed for 3855 RA patients (2576 women, mean age ±SD=60±15) at their first diagnosis visit and for 3062 RA patients (2313 women, mean age ±SD=57±14) at the start of their first biologic. Similar results for all subsequently described analyses were obtained at both time points. The correlation coefficient and 95% confidence interval (95%CI) between the indexes and age were 0.093 (0.063-0.124) for DAS28ESR and 0.055 (0.025-0.085) for DAS28CRP at the first visit, while CDAI was not correlated to age. There was no difference between men and women for CDAI and DAS28CRP, while DAS28ESR presented a mean difference of 0.1 unit between men and women. The agreement between categories of disease activity was moderate: at the RA diagnosis visit, the kappa statistics and 95% CI were: 0.63 (0.61-0.65) between DAS28ESR and DAS28CRP, 0.59 (0.57-0.61) between DAS28ESR and CDAI, and 0.55 (0.53-0.57) between DAS28CRP and CDAI. About 25% of the patients were classified differently. The Bland-Altman plot revealed that the difference between DAS28ESR and DAS28CRP depended on sex and slightly increased with age.Conclusion: Factors related to patient demographics might influence the results of disease activity indexes. This has a potential to affect clinical decisions, as the definition into disease activity categories can differ depending on the score used. This suggests the need to consider sex and age when defining such categories and interpreting results from these indexes.
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| 5. |
- Forsblad-d'Elia, Helena, et al.
(author)
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Biomechanical properties of common carotid arteries assessed by circumferential two-dimensional strain and β stiffness index in patients with ankylosing spondylitis
- 2021
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In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 48:3, s. 352-360
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Ankylosing spondylitis (AS) is associated with an elevated risk of cardiovascular disease (CVD) related to atherosclerosis, preceded by arterial stiffness. We aimed to examine common carotid artery (CCA) biomechanical properties using ultrasound to calculate β stiffness index (indicating arterial stiffness) and, a more recently developed technique, two-dimensional (2D) speckle tracking strain (indicating arterial motion and deformation, strain) to 1) compare with age- and sex-matched controls and to 2) analyze relationships between strain and stiffness with disease characteristics and traditional risk factors for CVD in AS patients.METHODS: In this cross-sectional study, a cohort of 149 patients with AS, mean age 55.3±11.2 years, 102(68.5%) men, 146 (98%) HLA-B27 positive, were examined. Bilateral CCAs were examined for circumferential 2D strain and β stiffness index. A subgroup of 46 patients were compared with 46 age- and sex-matched controls, both groups without hypertensive disease, diabetes, myocardial infarction or stroke.RESULTS: Mean bilateral circumferential 2D strain was lower in AS patients compared with controls, 7.9±2.6% vs 10.3±1.9%, p<0.001 whereas mean bilateral β stiffness index was higher, 13.1±1.6mmHg/mm vs 12.3±1.3mmHg/mm, p=0.018. In multivariable linear regression analyses strain was associated with age, erythrocyte sedimentation rate, history of anterior uveitis and treatment with csDMARD and/or bDMARD (R2 0.33), while stiffness was associated with age (R2 0.19).CONCLUSION: Both CCA circumferential 2D strain and β stiffness index differed between AS patients and controls. Strain was associated with AS-related factors and age while stiffness with age, suggesting that the obtained results reflect different pathogenic vascular processes.
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| 6. |
- Hedenstierna, Louise, et al.
(author)
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Neither low social support nor low decision latitude at work is associated with disease remission among patients with rheumatoid arthritis : results from the Swedish EIRA study
- 2022
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In: Arthritis Research & Therapy. - : BioMed Central. - 1478-6362. ; 24:1
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 months in patients with rheumatoid arthritis (RA).METHODS: This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996-2015 and the Swedish Rheumatology Quality Register (SRQ, n = 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level.RESULTS: Having low social support (n = 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74-1.16), 12 (OR 0.96, 95%CI 0.75-1.23), or 60 (OR 0.89, 95%CI 0.72-1.10) months compared to not low social support (n = 2209). No association was observed for low (n = 212) versus not low (n = 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54-1.31), 12 (OR 0.81, 95%CI 0.56-1.16), or 60 (OR 1.37, 95%CI 0.94-2.01) months.CONCLUSION: In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.
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| 7. |
- Hofstedt, Oscar E., et al.
(author)
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Comparison of agreement between internet-based registration of patient-reported outcomes and clinic-based paper forms within the Swedish Rheumatology Quality Register
- 2019
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In: Scandinavian Journal of Rheumatology. - : TAYLOR & FRANCIS LTD. - 0300-9742 .- 1502-7732. ; 48:4, s. 326-330
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Journal article (peer-reviewed)abstract
- Objective: The Swedish Rheumatology Quality Register has implemented an internet-based method (PER) for registering patient-recorded outcome measures. The aim of this study was to compare the agreement between visual analogue scales (VASs) reported via PER and clinic-based reporting using paper forms.Methods: In a cross-sectional study (70 patients), the results of 79 registrations of VASs for global health, pain, and fatigue from PER were compared with corresponding clinic-based paper registrations. For patients with polyarthritis, 28-joint count Disease Activity Scores (DAS28) were computed. Patients with axial disease also completed Bath Ankylosing Spondylitis Disease Activity Index and Functional Index (BASDAI and BASFI) questionnaires. Mean differences and intraclass correlation coefficients (ICCs) were calculated. Agreement was visualized using Bland-Altman plots.Results: No statistically significant differences in VASs were found comparing PER and paper forms for VAS Global, VAS Pain, and VAS Fatigue (p=0.295, 0.463, and 0.288, respectively). ICCs for VAS Global, Pain, and Fatigue ranged from 0.889 to 0.952, indicating excellent agreement. Bland-Altman plots for VAS did not show any proportional bias. The mean difference for DAS28 calculated by VASs from paper vs PER was -0.02 (n=65, p =0.660), and the mean difference for BASDAI was 0.04 (n=11, p =0.742). ICCs for DAS28 and BASDAI were 0.962 and 0.985, respectively. Of the participating patients, 60% preferred PER.Conclusion: Internet-based reporting for patient-reported outcomes in a clinical setting resulted in similar data for VASs and corresponding disease activity scores to clinic-based reporting on paper forms.
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| 8. |
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| 9. |
- Hörnberg, Kristina, et al.
(author)
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Individual regression modelling of spinal mobility measurements in long-term ankylosing spondylitis : In-depth analyses with comparison to norm data
- 2023
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In: Arthritis care & research. - : John Wiley & Sons. - 2151-464X .- 2151-4658. ; 75:4, s. 793-800
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Journal article (peer-reviewed)abstract
- Objectives: Normal age-related decline and temporary restrictions in mobility complicate the understanding of spinal mobility deterioration over time in patients with ankylosing spondylitis (AS). In this study, we aimed to determine whether spinal mobility deterioration occurred linearly in patients with AS. We also aimed to compare patterns of change with corresponding age-related normal values and analyze variations in temporary fluctuations in mobility measurements over time.Methods: We included 111 men and 30 women (median age 20.9 years at symptom onset), who were followed for median 34 years since symptom onset. This resulted in 9 697 spinal mobility measurements for analysis. Individual linear regression models for development of lateral spinal flexion (LSF), 10 cm Schober test (ST10), chest expansion (CE), and cervical rotation (CR) were analyzed and compared with normal age-related decline over time.Results: The median values for the constants of all measurements were significantly lower than the norm data. However, LSF, ST10, and CE followed a yearly linear decline comparable to the norm data, whereas CR declined about twice as fast as expected from the norm data (beta median [25th-75th percentile]: -0.62° [-1.16°, -0.22°] and -0.35° [-0.35°, -0.35°]), respectively. Temporary fluctuations in LSF and CE were significantly higher during the early phase of the disease, with decreasing residuals over time.Conclusion: Based on median constants of our data, mobility restrictions related to AS seem to mainly occur during the first years of disease, indicating a narrow window of opportunity for prevention.
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| 10. |
- Innala, Lena, 1060-, et al.
(author)
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Co-morbidity in patients with early rheumatoid arthritis - inflammation matters
- 2016
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In: Arthritis Research & Therapy. - : BioMed Central. - 1478-6362. ; 18
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Journal article (peer-reviewed)abstract
- 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.
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| 11. |
- Izadi, Zara, et al.
(author)
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Environmental and societal factors associated with COVID-19-related death in people with rheumatic disease : an observational study
- 2022
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In: The Lancet Rheumatology. - : Elsevier. - 2665-9913. ; 4:9, s. e603-e613
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Journal article (peer-reviewed)abstract
- Background: Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally.Methods: In this observational study, we derived individual-level data on adults (aged 18–99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death.Findings: 14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 μg/m3 [95% CI 1·01–1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10–1·30]; p<0·0001), and population mobility (1·03 per 1% increase in number of visits to grocery and pharmacy stores [1·02–1·05]; p<0·0001 and 1·02 per 1% increase in number of visits to workplaces [1·00–1·03]; p=0·032) were independently associated with higher odds of mortality. Number of hospital beds (0·94 per 1-unit increase per 1000 people [0·88–1·00]; p=0·046), human development index (0·65 per 0·1-unit increase [0·44–0·96]; p=0·032), government response stringency (0·83 per 10-unit increase in containment index [0·74–0·93]; p=0·0018), as well as follow-up time (0·78 per month [0·69–0·88]; p<0·0001) were independently associated with lower odds of mortality. These factors sufficiently explained country-level variations in death attributable to COVID-19 (intraclass correlation coefficient 1·2% [0·1–9·5]; p=0·14).Interpretation: Our findings highlight the importance of environmental and societal factors as potential explanations of the observed regional disparities in COVID-19 outcomes among people with rheumatic disease and lay foundation for a new research agenda to address these disparities.
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| 12. |
- Jönsson, Elias, et al.
(author)
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Pulmonary fibrosis in relation to genetic loci in an inception cohort of patients with early rheumatoid arthritis from northern Sweden
- 2022
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In: Rheumatology. - : British Society for Rheumatology. - 1462-0324 .- 1462-0332. ; 61:3, s. 943-952
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Pulmonary manifestations in RA are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA, has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors.METHODS: A total of 1466 early RA patients were consecutively included and followed prospectively from the index date until death or 31 December 2016. Clinical and laboratory data and treatment were continuously registered according to the Swedish Rheumatology Quality Register. DNA was available from 1184 patients and 571 151 genome-wide single-nucleotide polymorphisms (SNPs) were analysed. Thirteen identified genetic variants were extracted. At follow-up, the patients answered a questionnaire regarding disease progression and lung involvement that was validated by reviewing medical records and analysing radiological examinations.RESULTS: The prevalence of PF was 5.6% and the annualized incidence rate was 5.0/1000 (95% CI 3.80, 6.54). Four SNPs were associated with PF in RA: rs35705950 [MUC5B; OR 2.5 (95% CI 1.5, 4.0), adjusted P-value = 0.00016, q-value = 0.0021]; rs111521887 [TOLLIP; OR 1.9 (95% CI 1.3, 2.8), adjusted P-value = 0.0014, q-value = 0.0092]; rs2609255 [FAM13A; OR 1.7 (95% CI 1.1, 2.5), adjusted P-value = 0.013, q-value = 0.055] and rs2736100 [TERT; OR 1.5 (95% CI 1.0, 2.2), adjusted P-value = 0.046, q-value = 0.15]. Older age and RF positivity were associated with increased risk, while MTX treatment was associated with a lower risk of PF.CONCLUSIONS: Development of PF in an inception cohort of RA patients was associated with 4 of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF positivity were of limited importance in PF development.
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| 13. |
- Ljung, Lotta, 1964-, et al.
(author)
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Addressing the hardest endpoint
- 2020
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In: Rheumatology. - : OXFORD UNIV PRESS. - 1462-0324 .- 1462-0332. ; 59:3, s. 462-463
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Journal article (other academic/artistic)
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| 14. |
- Ljung, Lotta, 1964-
(author)
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Aspects on inflammation and cardiovascular comorbidity in rheumatoid arthritis
- 2012
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Doctoral thesis (other academic/artistic)abstract
- There is an increased risk for cardiovascular (CV) comorbidity among patients with rheumatoid arthritis (RA), with premature atherosclerosis, and a higher incidence of CV events, compared with the general population. Disease related factors add to the CV risk, and interact with the traditional CV risk factors. The underlying mechanism for this is not completely understood. In active RA there is a loss of muscle mass and an increase in body fat content. Production of cytokines, i.e., adipokines, in the adipose tissue could link the inflammation with the CV system. Control of the inflammation has been suggested to modify the CV risk in RA, and the recently introduced biological drugs, such as the tumor necrosis factor inhibitors (TNFi), have opened up new treatment opportunities. The aim of this thesis was to evaluate aspects of the interaction between inflammation and CV comorbidity in RA using biochemical and epidemiological methods.MethodsIn the first two studies, patients with established RA were examined for clinical disease activity, and blood samples were analysed for cytokines and adipokines using ELISAs and multiplex technology. In Study I (n RA=23) anthropometric measurements were assessed and in Study II (n RA=51) measurements of intima-media thickness (IMT), and endothelial function (FMD). From a subgroup of patients (Study II, n RA=13) samples of abdominal subcutaneous adipose tissue (SAT) were analysed for content of adipokines. In study III and IV associations between treatment with TNFi and acute coronary syndromes (ACS) were analysed using data from the Swedish Rheumatology Register; in Study III regarding early RA (n TNFi exposed=1,271, n bionaïve RA=4,729), and in Study IV comprising patients with RA of all stages (n TNFi exposed=7,213, n bionaïve RA=17,769) and with a matched general population comparator cohort (n=32,161). Associations between response to TNFi therapy and risk for ACS in the early RA cohort were evaluated in a nested case-control design (cases n=24, controls n=81).ResultsSerum levels of the cytokines/adipokines interleukin-1 receptor antagonist (IL-1Ra), IL-6, osteopontin, visfatin and TNF were increased in patients compared with controls (p≤0.001-0.036). The amount of TNF receptor II extracted from SAT was greater in patients (p=0.006). The serum (s-) levels of IL-1Ra correlated with s-leptin (r=0.71, p≤0.001) and s-haptoglobin in RA patients (r=0.56, p≤0.01). The result from a factor analysis indicated IL-1Ra to be associated with both adipose tissue and inflammation. Levels of s-visfatin (p=0.019) and s-IL-1Ra (p=0.023), respectively, were positively associated with IMT independently of inflammatory activity and CV risk factors. PAI-1 and MCP-1 extracted from SAT showed inverse associations with IMT.Patients with RA, whether exposed to TNFi or bio-naïve, had a doubled risk for ACS compared with the general population; HR 2.09 (95%CI 1.58-2.76) and 1.80 (1.49-2.17), respectively. No significant associations between risk for ACS and TNFi exposure were detected after adjustments; HR 0.80 (0.52-1.24) in early RA and HR 1.08 (0.82-1.41) in RA of any duration. Furthermore, no association between the risk for ACS and response to TNFi treatment in patients with early RA was observed, OR 1.5 (0.3-6.9).ConclusionsThe results indicate that cytokines/adipokines may have a role in the development of atherosclerosis in RA patients. A continuing increase in the risk of ACS in RA compared with the general population, despite modern therapeutic strategies, was noted. Neither exposure nor response to treatment with TNFi was associated with any modification of the risk for ACS.
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| 15. |
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| 16. |
- Ljung, Lotta, 1964-, et al.
(author)
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Incidence and predisposing factors of extra-articular manifestations in contemporary rheumatoid arthritis
- 2024
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In: European journal of internal medicine. - 0953-6205 .- 1879-0828.
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Journal article (peer-reviewed)abstract
- Objective: Rheumatoid arthritis [RA) is a chronic inflammatory disease, with potential for extra-articular manifestations (ExRA). The incidence and predisposing factors for ExRA and the mortality were evaluated in an early RA inception cohort.Methods: Patients (n = 1468; 69 % females, mean age (SD) 57.3(16.3) years) were consecutively included at the date of diagnosis, between 1 January 1996 and 31 December 2016, and assessed prospectively. In December 2016 development of ExRA was evaluated by a patient questionnaire and a review of medical records. Cumulative incidence and incidence rates were compared between 5-year periods and between patients included before and after 1 January 2001. Cox proportional hazard regression models were used to identify predictors for ExRA, and models with ExRA as time-dependent variables to estimate the mortality.Results: After a mean (SD) follow-up of 9.3(4.9) years, 238 cases (23.3 %) had ExRA and 151 (14.7 %) had ExRA without rheumatoid nodules. Most ExRA developed within 5 years from diagnosis. Rheumatoid nodules (10.5 %) and keratoconjunctivitis sicca (7.1 %) were the most frequent manifestations, followed by pulmonary fibrosis (6.1 %). The ExRA incidence among more recently diagnosed patients was similar as to the incidence among patients diagnosed before 2001. Seropositivity, smoking and early biological treatment were associated with development of ExRA. After 15 years 20 % had experienced ExRA. ExRA was associated with increased mortality, HR 3.029 (95 % CI 2.177–4.213).Conclusions: Early development of ExRA is frequent, particularly rheumatoid nodules. Predisposing factors were age, RF positivity, smoking and early biological treatment. The patients with ExRA had a 3-fold increase in mortality.
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| 17. |
- Ljung, Lotta, 1964-, et al.
(author)
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Low-energy fractures in rheumatoid arthritis - associations with genes and clinical characteristics
- 2019
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78, s. 344-345
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Journal article (other academic/artistic)abstract
- Background: Patients with rheumatoid arthritis (RA) have increased risk of osteoporosis and low-energy fractures. Several genes associated with bone mineralization, osteoporosis or risk of fracture in the general population have been identified.Objectives: To analyse the association between nine selected SNPs and the risk of low-energy fracture, taking clinical patient characteristics into account.Methods: We identified a cohort of patients (n=896, 70% women, age at inclusion 60.0±14.8 years) with RA according to ACR criteria from the catchment area of the register of Umeå injury database, Umeå, Sweden, which enabled identification of low-energy fractures (n=254). The follow-up (mean 8.8±6.1 years, total 7928 person-years) started two years after RA diagnosis but not earlier than January 1, 1993 and ended at the first of December 31, 2011, death or the first low-energy fracture. Nine SNPs were analysed in all patients with available DNA-samples (n=667) using KASPTM genotyping assays (LGC genomics Ltd, Hoddesdon, UK): rs3801387 (WNT16), rs6666455 (SOAT), rs3736228 (LRP5), rs4796995 (FAM210A), rs4792909 (SOST), rs2062377 (TNFRSF11B/OPG), rs884205 (TNFRSF11A/RANK), rs9533090 (TNFSF11/RANKL), and rs1373004 (DKK1). Anti-CCP was analysed and clinical patient characteristics (duration of RA, ever smoking, disease activity the first two years after RA diagnosis, and joint erosions) were extracted from patient files. Associations between the risk of fracture and risk alleles in the cohort were evaluated using Kaplan-Meier curves (K-M) and Cox proportional hazards models: crude, adjusted for age and sex, and for clinical patient characteristics.Results: The SNPs: rs1373004, rs4792909, and rs2062377 were associated with the risk of fracture in K-M analyses (Figure 1). For the other genes no significant associations were observed. Patients carrying the risk allele of rs1373004 (22.6% of the patients), or who were homozygous for the risk allele of SNP rs4792909 (38.6%), had a >50% higher risk of low-energy fracture compare to other patients, irrespectively of disease characteristics (Table 1). The association between rs2062377 and the risk of fracture was not independent of clinical patient characteristics (Table 1).
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| 18. |
- Ljung, Lotta, 1964-, et al.
(author)
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Methotrexate in Our Hearts
- 2019
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In: Journal of Rheumatology. - : Journal of Rheumatology Publishing Company Limited. - 0315-162X .- 1499-2752. ; 46:5, s. 447-449
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Journal article (other academic/artistic)
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| 19. |
- Strangfeld, Anja, et al.
(author)
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Factors associated with COVID-19-related death in people with rheumatic diseases : results from the COVID-19 Global Rheumatology Alliance physician-reported registry
- 2021
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80:7, s. 930-942
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Journal article (peer-reviewed)abstract
- Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases.Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category.Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death.Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.
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| 20. |
- Sundström, Björn, 1968-, et al.
(author)
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Consumption of dairy products and risk of rheumatoid arthritis among women : a population-based prospective cohort study
- 2019
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78, s. 1047-1048
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Journal article (other academic/artistic)abstract
- Background: Conflicting results have been reported regarding the association between consumption of milk and dairy products and the risk for development of rheumatoid arthritis (RA).Objectives: The aim of this study was to investigate the association between consumption of milk and dairy products and the development of RA in a large population-based cohort of women.Methods: In a prospective cohort study 35,600 women aged 48-83 years, from the Swedish Mammography Cohort (SMC), were followed between 2003 and 2015. Consumption of dairy products was assessed in 1997 at a mean age of mean age of 61.5 years (SD 9.1 years) with a 96-item self-administered questionnaire. The risk (hazard ratio; HR) of RA development associated with consumption of dairy products was estimated using Cox proportional hazard regression models with adjustment for age, alcohol intake, smoking, energy intake, meat and fish consumption.Results: During the follow-up of 12 years, 368 individuals were identified with a new diagnosis of RA. Comparing high consumption with low consumption of dairy products, no association between consumption of dairy products and the development of RA was observed: HR for the fully adjusted model=1.12 (95% CI: 0.78-1.59 (Table 1). Also when evaluating milk and cheese consumption separately, no association with the risk of RA was observed: HR for the highest milk consumption=1.10 (95% CI: 0.82-1.44) and highest cheese consumption HR=1.20 (95% CI: 0.81-1.79), compared with low consumption (fully adjusted models, table 1).Conclusion: In this large population-based cohort study, consumption of dairy products was not associated with risk to develop RA.
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| 21. |
- Sundström, Björn, 1968-, et al.
(author)
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Consumption of Meat and Dairy Products Is Not Associated with the Risk for Rheumatoid Arthritis among Women : A Population-Based Cohort Study
- 2019
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In: Nutrients. - : MDPI. - 2072-6643. ; 11:11
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Journal article (peer-reviewed)abstract
- Diet has gained attention as a risk factor for the development of rheumatoid arthritis (RA), especially with regards to food of animal origin, such as meat and dairy products. By using data from national patient registers and dietary data from a large prospective population cohort, the Swedish Mammography Cohort, we aimed to investigate whether the consumption of meat and dairy products had any impact on the risk of subsequent development of RA. During 12 years of follow-up (January 2003-December 2014; 381, 456 person-years), 368 patients with a new diagnosis of RA were identified. No associations between the development of RA and the consumption of meat and meat products (hazard ratio [HR] for the fully adjusted model: 1.08 [95% CI: 0.77-1.53]) or the total consumption of milk and dairy products (HR for the fully adjusted model: 1.09 [95% CI: 0.76-1.55]) were observed. In conclusion, in this large prospective cohort of women, no associations were observed between dietary intake of meat and dairy products and the risk of RA development.
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| 22. |
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| 23. |
- Sundström, Björn, 1968-, et al.
(author)
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Long-Term Spinal Mobility in Ankylosing Spondylitis : A Repeated Cross-Sectional Study
- 2020
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In: Arthritis care & research. - : John Wiley & Sons. - 2151-464X .- 2151-4658. ; 72:7, s. 1022-1028
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Journal article (peer-reviewed)abstract
- Objective: To evaluate the course of impaired spinal mobility in patients with long‐standing well‐defined ankylosing spondylitis (AS ).Methods: Data from 232 patients with AS (186 men, 46 women) and 3,849 clinical measurements performed between February 1980 and June 2016 were analyzed. Lateral spinal flexion (LSF ), the 10‐cm Schober test, chest expansion (CE ), and cervical rotation measurements were stratified by disease duration at 10‐year intervals and compared with published age‐ and height‐adjusted spinal mobility reference intervals as well as with fixed reference values commonly used in clinical practice.Results: After 10 years of AS , most patients exhibited at least 1 measurement, most commonly LSF , that was under the 2.5th percentile of the adjusted reference interval (53% of men, 65% of women). In all measurements except CE , there were significant linear increases in the proportion of patients during 40 years of disease duration who exhibited impaired mobility. Measured LSF values <2.5th percentile (mean 14.8 cm) after 10 years were associated with further spinal mobility impairments later in the disease course. Fixed reference values yielded higher proportions of patients with impaired mobility compared with adjusted reference intervals.Conclusion: Impaired spinal mobility in AS is common after a 10‐year disease duration. LSF below the 2.5th percentile at 10 years appeared to be associated with a worse prognosis. Fixed reference values overestimated spinal mobility impairments in AS and should be avoided.
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| 24. |
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| 25. |
- Södergren, Anna, 1977-, et al.
(author)
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Characteristics and outcome of a first acute myocardial infarction in patients with ankylosing spondylitis
- 2021
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In: Clinical Rheumatology. - : Springer Science and Business Media LLC. - 0770-3198 .- 1434-9949. ; 40, s. 1321-1329
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Journal article (peer-reviewed)abstract
- Objectives To study clinical characteristics, mortality, and secondary prevention, after a first incident acute myocardial infarction (AMI) in patients with ankylosing spondylitis (AS) compared with the general population. Methods In total, 292 subjects with AS and a first AMI between Jan 2006 and Dec 2014 were identified using the Swedish national patient register. Each subject was matched with up to 5 general population comparators per AS-patient (n = 1276). Follow-up started at the date of admission for AMI and extended until death or 365 days of follow-up. Cox regression was used to assess mortality in two time intervals: days 0-30 and days 31-365. For a subgroup with available data, clinical presentation at admission, course, treatment for AMI, and secondary prevention were compared. Results During the 365-day follow-up, 56/292 (19%) AS patients and 184/1276 (14%) comparators died. There were no difference in mortality due to cardiovascular-related causes, although the overall mortality day 31-365 was increased among patients with AS compared with comparators (HR [95% CI] = 2.0 [1.3;3.0]). At admission, AS patients had a higher prevalence of cardiovascular comorbidities compared with comparators. At discharge, patients with AS were less often prescribed lipid-lowering drugs and non-aspirin antiplatelet therapy. Conclusions Patients with AS tend to have a higher comorbidity burden at admission for first AMI. The mortality after a first AMI due to cardiovascular-related causes does not seem to be elevated, despite an increased overall mortality during days 31-365 among patients with AS compared with the general population.
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| 26. |
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| 27. |
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| 28. |
- Westerlind, Helga, et al.
(author)
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Siblings of patients with rheumatoid arthritis are at increased risk of acute coronary syndrome
- 2019
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78:5, s. 683-687
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Journal article (peer-reviewed)abstract
- Objectives: To investigate a potential shared susceptibility between rheumatoid arthritis (RA) and acute coronary syndrome (ACS) by estimation of the risk of ACS among full siblings of patients with RA.Methods: By linking nation-wide Swedish registers, we identified a cohort of patients with new-onset RA 1996–2016, age- and sex-matched (5:1) general population comparator subjects, full siblings of RA and comparator subjects, and incident ACS events through 31 December 2016. We used Cox regression to estimate the HR of ACS among patients with RA and the siblings of patients with RA versus the general population, overall and stratified by RA serostatus. We explored the impact of traditional cardiovascular (CV) risk factors on the observed associations.Results: We identified 8109 patients with incident RA, and 11 562 full siblings of these. Compared with the general population, the HR of ACS in RA was 1.46 (95% CI 1.28 to 1.67) and 1.22 (95% CI 1.09 to 1.38) among their siblings. The increased risks seemed confined to seropositive RA (patients: 1.52 [1.30 to 1.79], their siblings: 1.27 [1.10 to 1.46]); no significant risk increase was observed among siblings of patients with seronegative RA (HR 1.13 [95% CI 0.92 to 1.39]). Adjustment for 19 traditional CV risk factors did not appreciably alter these associations.Conclusion: Siblings of patients with RA are at increased risk of ACS, suggesting shared susceptibility between RA and ACS, indicating the need and potential for additional cardio-preventive measures in RA (and their siblings).
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