| 1. |
- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 4. |
- Westerlind, H, et al.
(författare)
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THE ASSOCIATION BETWEEN AUTOANTIBODIES AND RISK FOR VENOUS THROMBOEMBOLIC EVENTS AMONG PATIENTS WITH RHEUMATOID ARTHRITIS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 514-515
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease, including venous thromboembolic events (VTE)1. The reason behind the increased VTE risk is incompletely understood, but inherent features of RA, such as RA specific autoantibodies, could potentially play a role. For example, studies have linked occurrence and levels of rheumatoid factor (RF) in the general population to increased VTE risk2. We and others have demonstrated an association between ACPA and risk of later ischemic cardiovascular events3. There are also potential mechanistic links; citrullinated fibrinogen (cFib) has been associated to clot stability4.ObjectivesWe aimed to examine the association between anti-modified protein antibodies (AMPAs) and risk of VTE in RA.MethodsWe included 2809 individuals newly diagnosed with RA and included in the Swedish EIRA study 1996-2009. Through linkage to nationwide health care registers we identified past and incident events of VTE based on validated ICD code algorithms. We centrally typed baseline sera for anti-CCP2, 20 different ACPA sub-specificities, RF isotypes, carbamylated antibodies and 10 additional post-translational modifications. We followed all individuals from RA diagnosis up until their first ever VTE event, migration, death or end of study (2020-12-31) whichever occurred first. We used a Cox regression to estimate hazard ratios (HR) with 95% confidence intervals (CI). Individuals with a history of a VTE event (n=27) at RA diagnosis were excluded.ResultsWe included 2782 individuals; 72% were women, median age at RA diagnosis was 54 years (inter quartile range (IQR) 18 years) and median follow-up time was 15.5 (IQR 6.8) years. During follow-up 177 incident VTE events were observed corresponding to an incidence of 5.0 per 1,000 person years.1797 (64.6%) patients were positive for IgG anti-CCP2 and the HR for VTE (vs. being negative for anti-CCP2) was 1.33 (95%CI 1.00-1.78). The risk of VTE increased with the level of anti-CCP2, with an HR of 1.49 (95%CI 0.99-2.22) for the group with extreme levels compared to those negative for anti-CCP2 (p-value for trend 0.048). For IgA anti-CCP2 the HR was 1.35 (95% CI 0.99-1.84) when comparing those expressing IgA anti-CCP2 against those who did not.Of 20 ACPA fine-specificities studied, 18 occurred with a frequency > 10% in our sample. The median number of fine-specificities expressed was 6 (IQR 11). The risk of VTE increased with the number of ACPA fine-specificities expressed (p-value for trend 0.033). At the 0.05 significance level, two fine-specificities were each associated with VTE; cPept Z1 [HR=1.40 (95%CI 1.06-84)] and cPept-1 [HR=1.47 (95%CI 1.12-1.93)]. None of the six antibodies against cFib assessed were statistically significantly associated with VTE risk. No associations were observed for other AMPAs. Among the three RF isotypes, only IgM RF was statistically associated with VTE [HR=1.38 (95%CI 1.04-1.83)].ConclusionRA-related antibodies analysed in clinical practice (anti-CCP2 IgG, RF) are associated not only with risk of myocardial infarction, stroke and cardiovascular death as previously demonstrated but also with VTE. There were no clear specific signals with ACPA fine-specificities, other AMPAs, or IgA RA autoantibodies.References[1]Holmqvist ME,et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308(13):1350-6.[2]Meyer-Olesen CL, et al. Increased rheumatoid factor and deep venous thrombosis: 2 cohort studies of 54628 individuals from the general population. Clin Chem. 2015;61(2):349-59.[3]Westerlind H, et al. Anti-citrullinated protein antibody specificities, rheumatoid factor isotypes and incident cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheumatol. 2020.[4]Maners J, et al. A Mendelian randomization of gamma’ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke. Blood. 2020;136(26):3062-9.Disclosure of InterestsHelga Westerlind: None declared, Alf Kastbom: None declared, Johan Rönnelid: None declared, Monika Hansson: None declared, Lars Alfredsson: None declared, Linda Mathsson-Alm Employee of: LMA an employee of Thermo Fisher Scientific producing the ACPA sub-specificity test, Guy Serre: None declared, Martin Cornillet: None declared, Rikard Holmdahl Consultant of: historically several. Currently paid advisor for Lipum AB and Cyxone AB, Per-Johan Jakobsson Consultant of: UCB – Nov 2021 to Feb 2022., Karl Skriner: None declared, Holger Bang Employee of: HB is an employee of Orgentec Diagnostica, an IVRc company, Lars Klareskog: None declared, Saedis Saevarsdottir Employee of: SS is a part-time employee of deCODE genetics Inc., Karin Lundberg: None declared, Caroline Grönwall: None declared, Johan Askling Grant/research support from: AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB.
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| 9. |
- Brynedal, B, et al.
(författare)
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Molecular signature of methotrexate response among rheumatoid arthritis patients
- 2023
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Ingår i: Frontiers in medicine. - : Frontiers Media SA. - 2296-858X. ; 10, s. 1146353-
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but failure of satisfying treatment response occurs in a significant proportion of patients. Here we present a longitudinal multi-omics study aimed at detecting molecular and cellular processes in peripheral blood associated with a successful methotrexate treatment of rheumatoid arthritis.MethodsEighty newly diagnosed patients with RA underwent clinical assessment and donated blood before initiation of MTX, and 3 months into treatment. Flow cytometry was used to describe cell types and presence of activation markers in peripheral blood, the expression of 51 proteins was measured in serum or plasma, and RNA sequencing was performed in peripheral blood mononuclear cells (PBMC). Response to treatment after 3 months was determined using the EULAR response criteria. We assessed the changes in biological phenotypes during treatment, and whether these changes differed between responders and non-responders with regression analysis. By using measurements from baseline, we also tried to find biomarkers of future MTX response or, alternatively, to predict MTX response.ResultsAmong the MTX responders, (Good or Moderate according to EULAR treatment response classification, n = 60, 75%), we observed changes in 29 partly overlapping cell types proportions, levels of 13 proteins and expression of 38 genes during treatment. These changes were in most cases suppressions that were stronger among responders compared to non-responders. Within responders to treatment, we observed a suppression of FOXP3 gene expression, reduction of immunoglobulin gene expression and suppression of genes involved in cell proliferation. The proportion of many HLA-DR expressing T-cell populations were suppressed in all patients irrespective of clinical response, and the proportion of many IL21R+ T-cells were reduced exclusively in non-responders. Using only the baseline measurements we could not detect any biomarkers or prediction models that could predict response to MTX.ConclusionWe conclude that a deep molecular and cellular phenotyping of peripheral blood cells in RA patients treated with methotrexate can reveal previously not recognized differences between responders and non-responders during 3 months of treatment with MTX. This may contribute to the understanding of MTX mode of action and explain non-responsiveness to MTX therapy.
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| 10. |
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| 11. |
- Che, WI, et al.
(författare)
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Familial aggregation and heritability: a nationwide family-based study of idiopathic inflammatory myopathies
- 2021
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 80:11, s. 1461-1466
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Tidskriftsartikel (refereegranskat)abstract
- The magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM.MethodsThis is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM.ResultsWe included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings.ConclusionsIIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.
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| 21. |
- Diaz-Gallo, LM, et al.
(författare)
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Understanding interactions between risk factors, and assessing the utility of the additive and multiplicative models through simulations
- 2021
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:4, s. e0250282-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the genetic background of complex diseases requires the expansion of studies beyond univariate associations. Therefore, it is important to use interaction assessments of risk factors in order to discover whether, and how genetic risk variants act together on disease development. The principle of interaction analysis is to explore the magnitude of the combined effect of risk factors on disease causation. In this study, we use simulations to investigate different scenarios of causation to show how the magnitude of the effect of two risk factors interact. We mainly focus on the two most commonly used interaction models, the additive and multiplicative risk scales, since there is often confusion regarding their use and interpretation. Our results show that the combined effect is multiplicative when two risk factors are involved in the same chain of events, an interaction called synergism. Synergism is often described as a deviation from additivity, which is a broader term. Our results also confirm that it is often relevant to estimate additive effect relationships, because they correspond to independent risk factors at low disease prevalence. Importantly, we evaluate the threshold of more than two required risk factors for disease causation, called the multifactorial threshold model. We found a simple mathematical relationship (square root) between the threshold and an additive-to-multiplicative linear effect scale (AMLES), where 0 corresponds to an additive effect and 1 to a multiplicative. We propose AMLES as a metric that could be used to test different effects relationships at the same time, given that it can simultaneously reveal additive, multiplicative and intermediate risk effects relationships. Finally, the utility of our simulation study was demonstrated using real data by analyzing and interpreting gene-gene interaction odds ratios from a rheumatoid arthritis case-control cohort.
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| 22. |
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| 23. |
- Kronzer, VL, et al.
(författare)
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Allergic conditions and risk of rheumatoid arthritis: a Swedish case-control study
- 2022
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Ingår i: RMD open. - : BMJ. - 2056-5933. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- To determine the association of allergic conditions with incident rheumatoid arthritis (RA), especially in relation to smoking history and anti-citrullinated peptide antibody (ACPA) status.MethodsThis case–control study included 3515 incident RA cases and 5429 matched controls from the Epidemiological Investigation of Rheumatoid Arthritis study 1995 to 2016, including questionnaire-based information on eight allergic conditions composed from a list of 59 unique allergies. We used logistic regression and adjusted ORs (aOR) to assess the association between allergic conditions and risk of RA, adjusting for age, sex, residential area, body mass index, education, and smoking, and stratified by smoking and ACPA.ResultsA history of any reported allergy was equally common in RA (n=1047, 30%) as among population controls (n=1540, 29%), aOR 1.04, 95% CI 0.95 to 1.15. Metal, respiratory, food, plant/pollen and chemical allergies were not associated with risk of RA. By contrast, statistically significant associations were observed for animal dander allergy (6% vs 5%, aOR 1.37, 95% CI 1.03 to 1.82), especially in ACPA-positive RA (aOR 1.46 95% CI 1.06 to 2.01) and for atopic dermatitis, in particular for older and ACPA-negative RA (aOR 2.33, 95% CI 1.37 to 3.96 at age 80). Never smokers with allergic rhinitis also had increased risk of developing RA (aOR 1.30, 95% CI 1.00 to 1.68).ConclusionMost common allergies do not increase risk of RA, nor do they protect against RA. However, some allergic conditions, notably animal dander allergy, atopic dermatitis and allergic rhinitis, were associated with an increased risk for RA.
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| 24. |
- Kronzer, V. L., et al.
(författare)
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Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking
- 2021
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 73:1, s. 61-68
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Tidskriftsartikel (refereegranskat)abstract
- Objective The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. Methods Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past diagnoses of acute or chronic upper or lower respiratory disease. For each disease group, we estimated adjusted odds ratios (ORadj) with 95% confidence intervals (95% CIs) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education level both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. Results Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 (95% CI 0.8-1.7) for acute upper respiratory disease, 1.4 (95% CI 1.1-1.9) for chronic upper respiratory disease, 2.4 (95% CI 1.5-3.6) for acute lower respiratory disease, and 1.6 (95% CI 1.5-3.6) for chronic lower respiratory disease. These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA-positive or RF-positive RA than for ACPA-negative or RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). Conclusion Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.
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| 25. |
- Lehtonen, T, et al.
(författare)
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SLEEP PROBLEMS IN EARLY RHEUMATOID ARTHRITIS
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 614-614
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- It is well known that patients with established RA suffer from problems with sleep quality[1]. There are however few, if any, studies on sleep quality among newly diagnosed patients.Objectives:To investigate the sleep quality among patients newly diagnosed with RA.Methods:We used the Swedish study Epidemiological Investigation of RA (EIRA) including patients at the time of diagnosis, based on the 1987 ACR criteria during 2008-2016. At 1 and 3 years after diagnosis, the patients were sent a questionnaire in which they were asked to rate their sleep quality on 10 different questions. We then calculated 6 different sleep components consisting of insomnia, non-restorative sleep, sleep problems, general quality of sleep, if poor sleep affected the health and if they were getting enough sleep[2].Sleep problems were defined as mostly or always having problems with either of the following: falling asleep, many awakenings with difficulties to go back to sleep, waking up early or having disturbed/restless sleep. Insomnia was defined as answering mostly or always on either problem with falling asleep, many awakenings with difficulties to go back to sleep or waking up early, in combination with mostly or always being tired during the day.Having problems with non-restorative sleep was defined as mostly or always having trouble waking up or not feeling well rested when waking up. We defined having problem with not getting enough sleep, sleep quality affecting the health and poor sleep quality as reporting any of the two highest scores on the corresponding questions.We then calculated the proportion of people experiencing no problems at 1 or 3 years after RA diagnosis, developing problems, improving or always having problems with their sleep.Results:We identified 1483 patients with data at either one or both time points. The mean age was 59 years (IQR 19), and 1063 (72%) were women. At 1 year, 36% of the patients reported having at least one type of sleep problem, after 3 years, this figure was 29%. Over 20% of the patients reported having “Rather big” or “Very big” problems with sleep after one year (Table 1) and 31% had problems at one or both time points (Table 2). Disturbed sleep was a problem for their health in 20% of the patients and 11% reported having “poor” or “very poor” sleep quality at both times. Insomnia was experienced by 118 (10%) patients at 1 year and 112 (11%) at 3 years.Table 1.Sleep problems at 1 and 3 years after diagnosis of RA.1 year3 yearsInsomnia118 (9%)112 (11%)Not getting enough sleep102 (8%)113 (11%)Problems with sleep in general270 (22%)231 (22%)Sleep quality affecting health238 (19%)197 (19%)Poor sleep quality218 (17%)209 (20%)Problem with non-restorative sleep218 (17%)154 (14%)Table 2.Individuals experiencing no problems, developing problems, improving or always having problems with their sleep at 1 and 3 years after diagnosis of RA.No problems at any time pointImprovedDeveloped problemsProblems at both 1 and 3 yearsInsomnia702 (85%)43 (5%)46 (6%)39 (5%)Not getting enough sleep719 (86%)36 (4%)47 (6%)34 (4%)Problems with sleep in general576 (69%)81 (10%)78 (9%)103 (12%)Sleep quality affecting health616 (74%)65 (8%)70 (8%)85 (10%)Poor sleep quality623 (74%)57 (7%)66 (8%)91 (11%)Problem with non-restorative sleep654 (78%)71 (8%)46 (5%)67 (8%)Conclusion:In a population-based early RA cohort receiving today’s standard care, 30% of the patients reported some type of sleep problem during the first 3 years. Although this is a lower rate than has been reported in established RA, this is a significant proportion of RA patients, and these findings warrant further studies to closer identify the course of sleep problems and the factors influencing it such as pain.References:[1]Bourguignon C et al PMID 14596374[2]Akerstedt T et al PMID 18484368Acknowledgments:The authors wish to acknowledge the EIRA study group and the EIRA data collectors.Disclosure of Interests:Tiina Lehtonen: None declared, Torbjörn Åkerstedr: None declared, Lauren Lyne: None declared, Lars Klareskog: None declared, Saedis Saevarsdottir Employee of: Part-time at deCODE Genetics/Amgen Inc, working on genetic research unrelated to this project, Lars Alfredsson: None declared, Helga Westerlind: None declared
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| 26. |
- Li, Chunxia, et al.
(författare)
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Noncovalent microarrays from synthetic amino-terminating glycans : Implications in expanding glycan microarray diversity and platform comparison
- 2021
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Ingår i: Glycobiology. - : Oxford University Press. - 0959-6658 .- 1460-2423. ; 31:8, s. 931-946
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Tidskriftsartikel (refereegranskat)abstract
- Glycan microarrays have played important roles in detection and specificity assignment of glycan recognition by proteins. However, the size and diversity of glycan libraries in current microarray systems are small compared to estimated glycomes, and these may lead to missed detection or incomplete assignment. For microarray construction, covalent and noncovalent immobilization are the two types of methods used, but a direct comparison of results from the two platforms is required. Here we develop a chemical strategy to prepare lipid-linked probes from both naturally derived aldehyde-terminating and synthetic amino-terminating glycans that addresses the two aspects: expansion of sequence-defined glycan libraries and comparison of the two platforms. We demonstrate the specific recognition by plant and mammalian lectins, carbohydrate-binding modules and antibodies and the overall similarities from the two platforms. Our results provide new knowledge on unique glycan-binding specificities for the immune receptor Dectin-1 toward beta-glucans and the interaction of rotavirus P[19] adhesive protein with mucin O-glycan cores.
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| 27. |
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| 28. |
- Lyne, L, et al.
(författare)
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Sleep problems in rheumatoid arthritis over 12 years from diagnosis: results from the Swedish EIRA study
- 2022
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Ingår i: RMD open. - : BMJ. - 2056-5933. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Most studies of rheumatoid arthritis (RA) and sleep have focused on established RA. We here investigate sleep quality and sleep duration in patients with newly diagnosed RA and during 1–12 years after diagnosis.MethodsData were collected on sleep 1–12 years after diagnosis from patients diagnosed 1998–2018 in the Swedish study Epidemiological Investigation of RA. Six sleep domains (sleep problems, non-restorative sleep, insomnia, insufficient sleep, sleep quality perceived as poor and sleep considered a health problem); a global sleep score and time spent in bed were estimated. Using logistic regression, ORs were calculated for each sleep outcome by disease duration. We explored whether pain (low (Visual Analogue Scale=0–20 mm, reference), intermediate=21–70, high=71–100) or functional impairment (Health Assessment Questionnaire>1.0) was associated with problems.ResultsWe had sleep data on 4131 observations (n=3265 individuals). Problems with ≥1 sleep domain (global sleep score) was reported in 1578 observations (38%) and increased with disease duration (OR 1.04, 95% CI 1.02 to 1.07). Median time in bed was 8 hours (Q1-Q3: 7.5–9.0). High-grade pain increased the likelihood of sleep problems ~3–9 fold, and increased functional impairment ~4–8 fold.ConclusionIn this cohort of newly diagnosed patients with RA with access to the current treatment from diagnosis, we did not find any major problems with sleep, and existing sleep problems related mainly to pain and reduced function. Treatment of sleep problems in RA should be guided towards treating the underlying problem causing the sleep disturbance.
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| 31. |
- Pertsinidou, Eleftheria, et al.
(författare)
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Rheumatoid arthritis autoantibodies and their association with age and sex
- 2021
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Ingår i: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 39:4, s. 879-882
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To examine the association between individual rheumatoid arthritis (RA) autoantibodies, sex and age at RA onset. Methods. Anti-CCP2, IgA-, IgG- and IgM-RF were analysed centrally in baseline sera from 1600 RA patients diagnosed within one year of RA symptom onset. Cut-offs for RF isotypes were determined at the 98th percentile based on RA-free controls, close to the 98.4% anti-CCP2 specificity. Results. Anti-CCP2 was found in 1020 patients (64%), IgA RF in 692 (43%), IgG RF in 529 (33%) and IgM RF in 916 (57%) of the patients. When assessed one by one, anti-CCP2 and IgM RF were both associated with lower age at RA diagnosis. When assessed in one joint model, the association to IgM RF weakened and a strong association between IgA RF and higher age at RA diagnosis appeared. IgA RF and IgG RF associated with male sex, and IgM RF with female sex, with no difference for anti-CCP2. When the model was adjusted for sex, the association between IgM RF and age disappeared, whereas the strong associations between IgA RF and high age and between anti-CCP2 and low age at diagnosis remained. Further adjustments for smoking, shared epitope and inclusion year did not change the outcome. Univariate analyses stratified on anti-CCP2 and IgA RF status confirmed the findings. Conclusion. Anti-CCP associate with low, and IgA RF with high age at RA onset. RFs and anti-CCP2 display opposing association with sex. These results underscore that studies on RA phenotypes in relation to autoantibodies should accommodate age and sex.
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| 32. |
- Schelin, M. E.C., et al.
(författare)
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Widespread non-joint pain in early rheumatoid arthritis
- 2021
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 50:4, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the study was to assess the development of widespread non-joint pain (WNP) in a cohort of patients with early rheumatoid arthritis (RA), the associated health-related quality of life (HRQoL), and clinical and demographic risk factors for WNP. Method: Incident cases with RA, from the Swedish population-based study Epidemiological Investigation of Rheumatoid Arthritis (EIRA), with a follow-up of at least 3 years, constituted the study population. WNP was defined as pain outside the joints in all four body quadrants and was assessed at the 3 year follow-up. Patients who reported WNP were compared to patients without WNP regarding HRQoL, measured by the Short Form-36, at 3 years, and clinical and demographic characteristics at the time of RA diagnosis. Results: A total of 749 patients constituted the study sample, of whom 25 were excluded after reporting already having severe pain before RA diagnosis. At the 3 year follow-up, 8% of the patients reported having WNP as well as statistically significant worse HRQoL. At the time of RA diagnosis, the patients with WNP had worse pain and pain-related features, while no difference was seen in the inflammatory parameters. Conclusion: WNP occurs in a substantial subset of patients with RA, also early in the course of the disease, and the HRQoL for these patients is significantly reduced. Patients who develop WNP at 3 years are already distinguishable at the time of diagnosis by displaying more pronounced pain ratings together with an average level of inflammatory disease activity.
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| 34. |
- Sysojev, AO, et al.
(författare)
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A GENOME-WIDE INVESTIGATION OF PERSISTENCE TO TREATMENT WITH METHOTREXATE IN SWEDISH EARLY RHEUMATOID ARTHRITIS PATIENTS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 178-178
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Despite being the anchor drug for treating rheumatoid arthritis (RA), methotrexate (MTX) provides a good response only in some of the treated patients [1]. If MTX treatment outcome has a substantial genetic component, genetic variants could provide useful predictors for identification of patients likely to respond and remain on treatment. So far, studies have focused mainly on primary response, and attempts to explain the inter-patient variability through genetic variants have been inconclusive or underpowered [2,3].ObjectivesWe aimed to investigate whether there are genetic variants associated with persistence to treatment with MTX (at one and three years) in early RA, and to estimate any underlying heritability.MethodsWe conducted a genome-wide association study (GWAS) on persistence to treatment with MTX in DMARD-monotherapy. We included participants from the Epidemiological Investigation of RA (EIRA) study and the Swedish Rheumatology Quality Register’s biobank, diagnosed with early RA and treated with MTX as their first ever DMARD. Persistence to MTX was defined as remaining on treatment at one and three years, respectively, with no additional DMARDs added during that period. Estimation of SNP-based heritability was done using restricted maximum likelihood. We performed the analyses for all RA, and two disease subsets: those positive for either ACPA or rheumatoid factor, and those negative for both.ResultsAfter quality control, 3403 of an initial 3609 early RA patients of European ancestry and above five million SNPs remained for the primary analysis. Among these, 65% were persistent at one year, and 44% were persistent at three years. In secondary analysis we excluded 218 patients due to missing sero-status. Of the remaining, 72% were seropositive. No SNP reached genome-wide significance, neither for persistence at one nor at three years. The SNP-based heritability was estimated to 0.35 (95%CI 0.04-0.65) for persistence at one year and 0.09 (95%CI 0.00-0.37) for persistence at three years. Analyses stratified by sero-status provided results comparable to the main analysis with similar proportions of persistent patients and no SNP reaching genome-wide significance for any of the subgroups. Point estimates of heritability for persistence in the seropositive group at one year (h2 = 0.08, 95%CI 0.00-0.51) was lower than for seropositive persistence at three years (h2 = 0.19, 95%CI 0.00-0.62) while point estimates for the seronegative heritability were zero for both persistence outcomes.ConclusionDespite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The low heritability observed along with the lack of strong independent associations, may indicate that genetic influence from common genetic variants on persistence to MTX is minor, and of a polygenic nature.References[1]Saevarsdottir, S., et al., Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis, 2011. 70(3): p. 469-75.[2]Ling, S., J. Bluett, and A. Barton, Prediction of response to methotrexate in rheumatoid arthritis. Expert Rev Clin Immunol, 2018. 14(5): p. 419-429.[3]Szostak, B., et al., Using pharmacogenetics to predict methotrexate response in rheumatoid arthritis patients. Expert Opin Drug Metab Toxicol, 2020. 16(7): p. 617-626.AcknowledgementsThe authors would like to thank the participants of the EIRA study and the SRQ biobank as well as deCODE genetics for making this study possible.Disclosure of InterestsAnton Öberg Sysojev: None declared, Saedis Saevarsdottir Employee of: Part-time employee of deCODE genetics Inc., Lina M. Diaz-Gallo: None declared, Lars Alfredsson: None declared, Lars Klareskog: None declared, - SRQ Biobank Group: None declared, Thomas Frisell: None declared, Leonid Padyukov: None declared, Johan Askling Grant/research support from: Karolinska Institutet has entered into agreements with the following companies, with JA as PI: Abbvie, BMS, Eli Lilly, Galapagos, Janssen, Pfizer, Roche, Samsung Bioepis and Sanofi., Helga Westerlind: None declared
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- Tidblad, L, et al.
(författare)
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Comorbidities and treatment patterns in early rheumatoid arthritis: a nationwide Swedish study
- 2022
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Ingår i: RMD open. - : BMJ. - 2056-5933. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- To examine how comorbidities in patients with early rheumatoid arthritis (RA) associate with use of different disease-modifying antirheumatic drugs (DMARDs).MethodsWe used Swedish nationwide clinical and quality registers to collect comorbidity data for patients diagnosed with RA during 2006–2019 (n=13 505). We compared the use of DMARDs at diagnosis and after 1 year, in relation to comorbidity categories 5 years prior to RA diagnosis and overall comorbidity burden. For each comorbidity category, we also calculated adjusted ORs of being on treatment with other (or no) DMARDs compared with methotrexate (MTX) monotherapy 1 year after RA diagnosis.ResultsAt RA diagnosis, 68% (n=9178) of all patients were treated with MTX monotherapy, with the lowest proportion in patients with chronic kidney (CKD, 48%, n=50) and respiratory diseases (57%, n=413). At 1 year, most patients still received MTX monotherapy (<11% decrease, across all comorbidity categories). At 1 year, 13% received biological/targeted synthetic DMARDs, with the lowest proportion among patients with malignant diseases (OR=0.69, 95% CI=0.51 to 0.95). Being without DMARD at 1 year was more common among patients with CKD (OR=3.25, 95% CI=2.20 to 4.81), respiratory diseases (OR=1.83, 95% CI=1.32 to 2.53) or a history of hospitalisation due to infection (OR=1.47, 95% CI=1.23 to 1.75), and among patients with higher comorbidity burden and older age.ConclusionIn a nationwide setting with universal healthcare, most comorbid conditions do not limit the initiation or continuation of MTX or other DMARDs in early RA, although patients with certain comorbid conditions, higher comorbidity burden and higher age were somewhat less intensively treated.
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- Tidblad, L, et al.
(författare)
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COMORBIDITIES AT DIAGNOSIS OF RHEUMATOID ARTHRITIS
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 271-272
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Although many studies have reported an increased burden of comorbidities in patients with rheumatoid arthritis (RA), and their impact on RA outcomes, few studies have compared the pattern of comorbidities already at diagnosis of RA, in relation to the burden among matched control subjects. Only such a comparison can inform on which comorbidities are increased already before RA diagnosis, presumably due to overlapping causal factors, and which arise as a consequence of the RA disease or its treatment.Objectives:The aim of this study was to investigate the pattern of common chronic conditions in patients with RA, overall and stratified by serological status, at the time of diagnosis, compared to a matched control group reflective of the general population.Methods:This nationwide study included patients with a new-onset RA diagnosis, using data from the Swedish Rheumatology Quality register, from 2006 to 2015. We included 11,086 incident RA cases, of whom 62% were seropositive. From the Total Population Register, we identified 54,813 population controls, individually matched on age, sex and county of residence. Information about registered comorbidity diagnoses during the five years up until the RA diagnosis was retrieved from the Swedish National Patient Register. Information on dispersed drugs during the year up until the RA diagnosis was collected from the Prescribed Drug Register. Comorbidity diagnoses were grouped into 10 different categories (see table 1). Logistic regression was used to compare comorbidities between cases and controls, adjusted for the matching variables.Table 1.Relative risk of comorbidities at RA diagnosis, overall and by serological statusAll RASeropos RASeroneg RAComorbiditiesOR*95% CIOR*95% CIOR*95% CICardiovascular1.111.03–1.201.060.95–1.171.201.07–1.36Non-cardiac vascular1.030.98–1.091.030.96–1.101.060.97–1.16Respiratory1.581.44–1.741.741.54–1.961.351.15–1.59Gastrointestinal1.171.08–1.271.121.01–1.251.281.12–1.46Psychiatric0.870.82–0.920.870.80–0.930.960.87–1.06Nephrological0.900.71–1.150.890.63–1.250.960.68–1.36Infectious1.121.03–1.231.131.01–1.271.171.02–1.35Endocrine1.391.31–1.471.411.31–1.511.351.23–1.48Cancer0.880.79–0.970.810.71–0.930.930.80–1.10Neurological1.731.59–1.891.621.45–1.812.001.74–2.29*All ORs are adjusted for sex and age, and cases with RA are compared to their individually matched control subjects.Results:In seropositive as well as in seronegative RA, comorbidities within the respiratory (OR 1.58, 95% CI 1.44-1.74), gastrointestinal (OR 1.17, 95% CI 1.08-1.27), infectious (OR 1.12, 95% CI 1.03-1.23), endocrine (OR 1.39, 95% CI 1.31-1.47) and neurological (OR 1.73, 95% CI 1.59-1.89) categories were more common already at the time of RA diagnosis, compared to the matched population controls, as outlined in table 1. A history of cardiovascular disease was slightly increased among patients with seronegative RA (OR 1.20, 95% CI 1.07-1.36), and no increase was seen for non-cardiac vascular diseases. A history of psychiatric (OR 0.87, 95% CI 0.80-0.93) and cancer diagnoses (OR 0.81, 95% CI 0.71-0.93) was less common in seropositive RA vs. their matched controls. In terms of comorbidity burden, 15% of all RA patients had diagnoses from at least two of the ten comorbidity categories vs. 13% of the controls and 8% vs. 8% had diagnoses within three or more comorbidity categories.Conclusion:This large nationwide study demonstrates a marked increase in several comorbidities, in particular respiratory, endocrine and neurological diseases, already at, and before, the diagnosis of RA compared with age and sex matched controls, while psychiatric diagnoses are less common. These findings are important for the interpretation of comorbidity studies in established RA.Figure 1.Prevalence of comorbidities in Swedish patients with newly diagnosed RA compared to the matched controls * p < 0.05Disclosure of Interests:Liselotte Tidblad: None declared, Helga Westerlind: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma, Saedis Saevarsdottir Employee of: Part-time at deCODE Genetics/Amgen Inc, working on genetic research unrelated to this project
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- Westerlind, H, et al.
(författare)
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Is tea consumption associated with reduction of risk of rheumatoid arthritis? A Swedish case-control study
- 2021
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Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 23:1, s. 209-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTea is a popular beverage around the world and has properties that can affect the immune system. The association between tea consumption and the risk of rheumatoid arthritis (RA), a chronic autoimmune disease primarily affecting the joints, is not well studied and results are conflicting.MethodsWe collected data on tea consumption for 2237 incident RA cases diagnosed 2005–2018 and 4661 controls matched on age, sex, and residential area. Tea consumption was classified into no (0 cups/day), irregular (< 1 cup/day), regular (1–2 cups/day), and high (≥ 2 cups/day) consumption, and irregular consumption was used as the reference category. Missing data on tea consumption was classified as no consumers, and sensitivity analyses were performed to test this assumption. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, adjusting for smoking, coffee, alcohol, educational level, and body mass index. We also performed stratified analysis on sex, anti-citrullinated autoantibody (ACPA) status, and smoking habits.ResultsAmong the cases, we found 57.3% to be ever consumers of tea with 19.7 having a high tea consumption. Corresponding figures for the controls were 58.4% ever drinkers with 22.1% high tea consumers. High tea consumption had an inverse association to the risk of RA compared to irregular consumption [OR = 0.78 (95% CI 0.66–0.92)], but the association lost statistical significance in the adjusted model [adjusted OR (adjOR) = 0.85 (95% CI 0.71–1.01)]. Among non-tea consumers, a protective effect was also observed compared to irregular consumers [adjOR = 0.82 (95% CI 0.70–0.88)], but this association did not withstand sensitivity analysis, possibly due to bias. In the ACPA-positive group and among current smokers, a protective effect of tea consumption was observed among the high tea consumers [adjOR = 0.76 (95% CI 0.62–0.94) and adjOR = 0.60 (95% CI 0.38–0.95), respectively].ConclusionsThis study suggests a protective effect of high consumption of tea, among smokers and for ACPA-positive RA.Trial registrationNot applicable
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| 46. |
- Westerlind, H, et al.
(författare)
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IS TEA CONSUMPTION ASSOCIATED WITH RISK OF RHEUMATOID ARTHRITIS?
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 1059-1060
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Only few studies have looked at the association between tea consumption and risk of rheumatoid arthritis (RA) with inconclusive results.Objectives:To estimate the association between tea consumption and risk of RA in a large population-based case-control study.Methods:We used data from the Swedish Epidemiological Investigation of RA (EIRA), a population-based case-control study including incident RA cases with 2 controls randomly matched from the general population, based on age, sex and residential area at the date of diagnosis. All participants filled in a comprehensive questionnaire on lifestyle factors, including a 124-item food frequency questionnaire (FFQ). Data from October 2005 - May 2018 was used.Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression, overall and stratified by anti-citrullinated protein antibody (ACPA) and smoking status. We adjusted for smoking status, coffee and alcohol consumption, educational level and BMI. The dose-response trend of the association between tea consumption and risk of rheumatoid arthritis was estimated using restricted cubic spline with knots at 0, 0.29, and 2.29 cups per day. Missing tea values (44.8%) were imputed based on the zero-consumption assumption. A sensitivity analysis was performed to evaluate the influence of the assumption on the main result, with 70% of the missing randomly imputed as no consumption, and the remaining 30% randomly assigned to the other categories (10% per category).Results:We included 2237 cases and 4661 controls. Controls were more likely to drink ≥2 tea cups/day compared to RA cases (22.1% vs. 19.7%).The crude odds of developing RA was 22% lower (OR=0.78, 95% CI: 0.66-0.92) among those who consumed ≥2 tea cups/day compared to those who drank <1 cup/day (irregular drinkers). After adjustment for covariates, the inverse association was less pronounced and only borderline significant (OR=0.85, 95% CI: 0.71-1.01). A similar OR was observed among non-tea consumer (OR=0.82, 95% CI: 0.70-0.95). The odds of developing ACPA positive RA (but not ACPA negative) was statistically significant lower among participants drinking >=2 cups/day compared to irregular tea drinkers (OR=0.76, 95% CI: 0.62-0.94). In analyses stratified by smoking, an inverse association between tea intake and RA was found only among current smokers (OR=0.58, 95% CI: 0.37-0.92), while no association was found in never smoker. The sensitivity analysis showed results similar to the main analysis, although the OR in the no consumption category was not significant (OR=0.88, 95% CI: 0.76-1.02) while the OR in the highest category was statistically significant (OR=0.85, 95% CI: 0.73-0.99).Overall tea consumption0 cups/day<1 cup/day1-2 cups/day>=2 cups/dayOverall Number955/1941453/847388/845441/1028 OR crude*0.89 (0.77-1.03)Ref0.84 (0.71-1.00)0.78 (0.66-0.92) OR adjusted±0.82 (0.70-0.95)Ref0.87 (0.73-1.04)0.85 (0.71-1.01)ACPA positive Number637/1156321/527268/501277/630 OR adjusted0.81 (0.67-0.97)Ref0.88 (0.71-1.09)0.76 (0.62-0.94)ACPA negative Number312/571129/221119/251162/288 OR adjusted0.87 (0.66-1.14)Ref0.87 (0.63-1.19)1.07 (0.78-1.46)Never smokers Number290/859164/436142/433213/563 OR adjusted0.90 (0.72-1.14)Ref0.88 (0.68-1.15)1.04 (0.81-1.33)Current smokers Number296/37189/9659/7859/99 OR adjusted0.81 (0.57-1.14)Ref0.83 (0.52-1.31)0.58 (0.37-0.92)Figure 1.Dose-response odds ratio for risk of rheumatoid arthritis (RA) by tea consumption.Conclusion:In this large population-based case-control study, high tea consumption, as well as no consumption, was associated with a decreased risk to develop ACPA positive, but not negative, RA, when compared to irregular tea drinking (<1 cup/day). The inverse association between high tea consumption and RA was lowest in analyses restricted to current smokers.Disclosure of Interests:Helga Westerlind: None declared, Ida Palmqvist: None declared, Saedis Saevarsdottir Employee of: part-time employee of deCODE genetics, Lars Alfredsson: None declared, Lars Klareskog: None declared, Daniela Di Giuseppe: None declared
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| 48. |
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| 49. |
- Westerlind, H, et al.
(författare)
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Siblings of patients with rheumatoid arthritis have an increased mortality rate: a Swedish cohort study
- 2020
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Ingår i: RMD open. - : BMJ. - 2056-5933. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- To estimate the mortality among siblings of patients with rheumatoid arthritis (RA) and put any excess mortality among these in relation to the mortality among patients with RA.MethodsUsing prospective nation-wide registers, we identified patients diagnosed with new-onset RA 2001–2017 (n=8137), patients with prevalent RA 2006–2017 (n=25 464), matched general population comparator subjects to all RA patients (n=22 457/68 674) and full-siblings of all groups (n=28 878/91 546).We followed all cohorts until death, 31 December 2018, migration and (for non-RA subjects) RA diagnosis. We compared patients with RA versus the general population, and siblings of RA versus siblings of the general population using Cox regression, including adjustment for socio-economy.ResultsThe HR of death versus the general population was 1.11 (95% CI 1.01 to 1.22) for incident and 1.46 (95% CI 1.39 to 1.52) for prevalent patients with RA. The siblings of these patient groups were also at increased risk of death (HR=1.10, 95% CI 1.01 to 1.20 and 1.09, 95% CI 1.04 to 1.13, respectively), with little impact of adjustment for socio-economy.ConclusionThe mortality in RA is increased, but around one-fifth of this excess is present also among their siblings. Previous literature using general population rates for comparison has thus likely overestimated the direct impact on mortality attributable to RA. To bring down excess mortality in RA, optimal disease control is important but may not suffice.
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