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- Mathsson-Alm, L, et al.
(author)
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THE NORA PROJECT - PREDICTION OF THERAPY RESPONSE IN RHEUMATOID ARTHRITIS
- 2021
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 1090-1090
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Conference paper (other academic/artistic)abstract
- Personalized medicine in Rheumatoid arthritis (RA) especially regarding therapy response is still in early stages. The Nordic RA (NORA) project is aiming to improve the prediction of therapy outcome by combining established serologic marker with new markers, genetic information and patient-derived data.Objectives:As an initial step in the project the aim was to select clinically characterized patient cohorts and evaluate if changes or patterns in serological markers could predict therapy response and/or disease progress.Methods:The ARCTIC (Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen) study [1] was designed to compare two tight control treatment strategies for early Rheumatoid arthritis and was used as a first cohort. Plasma samples (n=1622) from 224 RA patients from the ARCTIC study were included and taken at baseline and 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 months from trial start, and analyzed for the presence of EliATM RF (IgM, IgA, IgG), anti-CCP (IgG, IgA) and anti-RA33 (IgM, IgA, IgG) autoantibodies, as well as Calprotectin using the EliA instrument platform (Phadia AB, Uppsala, Sweden). In addition, a custom-made multiplex chip (Thermo Fisher Scientific, Sweden) [2] was used for measurement of anti-IgG antibodies against RA-specific antigens (citrullinated, acetylated and carbamylated), and established CTD-markers (Connective Tissue Disease), e.g. Ro52/60 and dsDNA. The citrullinated peptides on the multiplex chip were both multiple as well as single citrullinated at different positions within the peptide sequence. Additionally, we included an ELISA to measure antibodies against native human collagen II [3].Results:The different single assays in the baseline samples varied between 7 – 80% positive test results, e.g. anti-CCP IgG 80%. For some patients we could see changes in levels for anti-CCP, RF and anti-RA33 in the follow up samples, which varied from negative to more than 3-10xULN (Upper Limit of Normal). For anti-CCP IgG we found 9 patients (4%), who changed from negative to positive (patient 1-5) or from positive to negative (patient 6-8), while patient 9 had a peak at visit 6 (=12 months) and declined afterwards (figure 1). In addition, the above mentioned 9 patients showed clear changes in signal strength for the markers included on the multiplex chip and followed a similar pattern as the anti-CCP IgG signal. Different antibody patterns against single citrullinated peptides were observed and number of ACPA-positive peptides correlated with IgG anti-CCP levels.Figure 1.Anti-CCP IgG value normalised to cutoff (blue line) for patient 1 to 9. The heatmap visualizes the change over time in anti-CCP IgG signal with dark blue showing negative results and orange/red showing results >5xULN.Anti-Collagen II antibodies (anti-CII) were detected in 15% of the baseline samples and in most cases declined over time. Two patients showed low baseline anti-CII levels that increased in the follow up samples. The changes in serological markers and the different reactivity patterns could possibly correlate with clinical outcome and define subgroups of patients with different response to therapy.Results could be repeated in RA patients from the NOR-VEAC [4] cohort. At baseline 73% of the 106 RA patients had a positive anti-CCP IgG result and 11 patients (10%) showed a significant change of anti-CCP IgG level over time.Conclusion:Different response patterns and changes in serological antibody levels over the first 24 months after RA diagnosis could possibly reveal subgroups of patients with different prognosis and response to treatment. Further evaluations in additional treatment cohorts and correlation with clinical data are ongoing.References:[1]Haavardsholm et al., BMJ 2016;354:i4205.[2]Hansson et al. Arthritis Research & Therapy 2012, 14:R201.[3]Manivel et al Ann Rheum Dis. 2017 Sep;76(9):1529-1536.[4]Mjaavatten et al., Arthritis Research & Therapy 2009, 11:R146.Acknowledgements:The NORA project is a NordForsk funded project.Disclosure of Interests:Linda Mathsson-Alm Employee of: Employee of Thermo Fisher Scientific, Isabel Gehring Employee of: Employee of Thermo Fisher Scientific, Maryam Poorafshar Employee of: Employee of Thermo Fisher Scientific, Johan Rönnelid: None declared, Johan Askling Grant/research support from: Research grants from Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB, mainly in the context of safety monitoring (ARTIS), Espen Haavardsholm: None declared, Hilde Berner Hammer: None declared
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- Westerlind, H, et al.
(author)
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THE ASSOCIATION BETWEEN AUTOANTIBODIES AND RISK FOR VENOUS THROMBOEMBOLIC EVENTS AMONG PATIENTS WITH RHEUMATOID ARTHRITIS
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 514-515
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Conference paper (other academic/artistic)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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- Brink, M, et al.
(author)
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PULMONARY FIBROSIS IN EARLY RHEUMATOID ARTHRITIS IN RELATION TO GENETIC LOCI AND INDIVIDUAL ACPA SPECIFICITIES
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 203-204
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Conference paper (other academic/artistic)abstract
- Pulmonary manifestations in rheumatoid arthritis (RA) are common comorbidities but the underlying mechanisms are largely unknown. We found in a previous study 3 SNPs associated with pulmonary fibrosis (PF); rs35705950 (MUC5B), rs111521887 (TOLLIP), and rs2609255 (FAM13A) besides age, rheumatoid factor positivity and methotrexate treatment.ObjectivesTo evaluate for the added value of a multiplex of anti-citrullinated peptide antibodies (ACPA) for the development of pulmonary fibrosis (PF) in an inception cohort of RA patients.MethodsA total of 1184 patients with early RA were consecutively included and followed prospectively from the date of diagnosis (index date) until death or until 31 December 2016. The diagnosis of PF was based on high resolution tomography. The presence of 21 ACPA fine specificities were analysed in plasma sampled at index date, using a custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden). Data on both ACPA and genetic data was available for 841 RA patients, of whom 50 developed PF. Associations were analysed using logistic regression analysis and presented as the odds ratio (OR) with the 95% confidence interval (CI). Models were adjusted for sex, age, DAS28 and presence of RF at RA diagnosis, smoking ever, and HLA-SE and in a second step for the three SNPs (.rs35705950, rs111521887 and rs2609255), respectively.ResultsIn unadjusted analyses eight ACPA reactivities were found associated with PF development (p< 0.05-0.001). The number of ACPA reactivities was related to PF development, both in crude and adjusted models (p<0.05 for both). In models concomitantly adjusted for the three SNPs (rs35705950, rs111521887 and rs2609255) respectively, in addition to mentioned adjustments the number of ACPA reactivities (p<0.05 for all three nmodels), Vim60-75 (p<0.05, in all three models), Fibβ62–78 (72) (p<0.001-p<0.05) and F4-CIT-R (p<0.01-p<0.05) were all found significantly associated to PF development irrespective of the SNPs.ConclusionThe development of PF in an inception cohort of RA patients was associated both with risk genes and, independently of the risk genes, the presence of certain ACPA, and the number of ACPA reactivities.References[1]Jönsson E, et al. Pulmonary fibrosis in relation to genetic loci in an inception cohort of patients with early rheumatoid arthritis from northern Sweden. Rheumatology (Oxford). 2021 May 16:keab441. doi: 10.1093/rheumatology/keab441.AcknowledgementsI have no acknowledgements to declare. The staff and patients at the departments of rheumatology in northern Sweden.Disclosure of InterestsNone declared
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- Elbagir, S, et al.
(author)
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ANTI-PHOSPHATIDYLSERINE/PROTHROMBIN ANTIBODIES AND VASCULAR EVENTS ASSOCIATE POSITIVELY WITH HLA-DRB1*13 AND NEGATIVELY WITH HLA-DRB1*03 IN SLE
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 658-659
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Conference paper (other academic/artistic)abstract
- Anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT) associate with thrombotic events (1). HLA-DRB1 alleles contribute to the occurrence of conventional antiphospholipid antibodies (aPL), including anti-beta2glycoprotein-I (beta2GPI) and anti-cardiolipin (CL) (2).ObjectivesWe investigated associations between anti-PS/PT and HLA-DRB1 alleles and thrombosis in patients with SLE. Conventional aPL were included for comparison.MethodsWe included 341 consecutive Swedish SLE patients, with information on general cardiovascular risk factors, including blood lipids, lupus anticoagulant (LAC) and thrombotic events. Anti-PS/PT, anti-beta2GPI and anti-CL of IgA/G/M isotypes were quantified in parallel using particle-based multi-analyte technology. The 99th percentiles among 162 age- and sex-matched populations controls were used as cutoffs. HLA-DRB1 typing was performed using sequence-specific primer PCR.ResultsAnti-PS/PT antibodies associated positively with HLA-DRB1*13 (odds ratio [OR] 2.7, P=0.002), whereas anti-beta2GPI and anti-CL antibodies associated primarily with HLA-DRB1*04 (OR 2.5, P=0.0005; Table 1). These associations remained after adjustment for other significant HLA-DRB1 alleles identified in Table 1 (Figure 1a and b) also for LAC (Figure 1c), and also after adjustment for age and gender (not shown). HLA-DRB1*13, but not DRB1*04, remained as an independent risk factor for thrombosis after adjustment for significant HLA alleles (Figure 1d), and also after adjustment for cardiovascular risk factors in stepwise regression (not shown). Mediation analysis showed that 31.3% of the HLA-DRB1*13-related risk for thrombosis was mediated by anti-PS/PT positivity. HLA-DRB1*03, on the other hand, associated negatively with thrombotic events (Figure 1d) as well as with all aPL (Figure 1a-c). HLA-DRB1*03 had thrombo-protective effect in aPL positive patients (Figure 1d). Additionally, HLA-DRB1*03 positivity was associated with a favourable lipid profile regarding high-density lipoprotein (median 1.4 vs. 1.2 mmol/L, p=0.02) and triglycerides (median 0.9 vs 1.1 mmol/L, p=0.04); whereas no other HLA-DRB1 alleles showed any associations to lipid levels.Table 1.Frequency of individual HLA DRB1 and associations with antibody phenotypes. Odds ratios (OR) and confidence intervals (CI) for being antibody positive given a specific HLA allele and corresponding p values were calculated using Chi2 tests, with significant associations underlined.HLA DRB1HLA-DRB1 n (%) total patientsAnti-PS/PT positive (any isotype) n=48OR (95%CI); PAnti-β2GPI or anti-CL positive (any isotype) n=96OR (95%CI); P*0141 (12.9%)4 (8.3%)0.6 (0.2-1.7); 0.311 (11.4%)0.8 (0.4-1.7); 0.6*03147 (46.5%)13 (27.1%)0.4 (0.2-0.7); 0.00433 (34.4%)0.5 (0.3-0.8); 0.006*0494 (29.7%)18 (37.5%)1.6 (0.8-2.9); 0.241 (42.7%)2.5 (1.5-4.1); 0.0005*0728 (8.9%)6 (12.5%)1.5 (0.6-4); 0.49 (9.4%)1 (0.4-2.4); 0.9*0828 (8.9%)6 (12.5%)1.6 (0.6-4.3); 0.39 (9.4%)1.2 (0.5-2.7); 0.7*099 (2.8%)1 (2.1%)0.7 (0.1-5.5); 0.72 (2.1%)0.6 (0.1-3.0); 0.5*107 (2.2%)0 (0)NA2 (2.1%)0.9 (0.2-4.6); 0.9*1127 (8.5%)6 (12.5%)1.6 (0.6-4.3); 0.38 (8.3%)0.9 (0.4-2.2); 0.8*127 (2.2%)0 (0)NA1 (1%)0.4 (0.05-3.7); 0.4*1379 (25%)21 (43.7%)2.7 (1.4-5.2); 0.00233 (34.3%)2 (1.2-3.4%); 0.01*146 (1.9%)2 (4.2%)3.7 (0.6-23); 0.12 (2.1%)1.4 (0.2-8.9); 0.8*15118 (37.3%)12 (48%)0.5 (0.2-0.9); 0.04527 (28.1%)0.5 (0.3-0.9); 0.01*168 (2.5%)1 (2.1%)0.8 (0.09-6.4); 0.84 (4.2%)2.2 (0.5-9.2); 0.2ConclusionHLA-DRB1*13 confers risk for both anti-PS/PT and thrombotic events in SLE. The association between HLA-DRB1*13 and thrombosis is largely, but not entirely, mediated through anti-PS/PT. Due to the negative association of HLA-DRB1*03 with aPL and the positive association with favourable lipid levels, HLA-DRB1*03 seems to identify a subgroup of SLE patients with reduced vascular risk.References[1]Elbagir S et al. Lupus 2021;30(8):1289.[2]Lundström E et al. Ann Rheum Dis 2013;72:1018.Disclosure of InterestsSahwa Elbagir: None declared, Lina M. Diaz-Gallo: None declared, Giorgia Grosso: None declared, Agneta Zickert: None declared, Iva Gunnarsson: None declared, Michael Mahler Employee of: Dr Mahler is employee of Werfen., Elisabet Svenungsson Speakers bureau: Dr Svennungson has obtained speaker’s fees from Janssen., Grant/research support from: Dr Svennungson has obtained research grant from Merck., Johan Rönnelid Speakers bureau: Dr Rönnelid has given paid lectures for Thermo Fisher Scientific., Consultant of: Dr Rönnelid has been a member of the Scientific Advisory Board for Thermo Fisher Scientific.
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- Gronwall, C, et al.
(author)
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THE RELATIONSHIP BETWEEN DIFFERENT IGG AND IGA ANTI-MODIFIED PROTEIN AUTOANTIBODIES IN RHEUMATOID ARTHRITIS
- 2021
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 206-207
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Conference paper (other academic/artistic)abstract
- Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), anti-acetylated (KAc), and anti-malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. By using RA patient single-cell derived monoclonal antibodies we have previously shown that individual ACPA clones recognize small distinct citrulline-containing epitopes giving them extensive multireactivity when these epitopes are found in many peptides and proteins. Moreover, certain CCP2+ multireactive ACPA clones bind also to cabamylated and acetylated autoantigens [1].Objectives:To provide a comprehensive evaluation of serum IgG and IgA autoreactivity to different post-translational modifications in RA.Methods:We analyzed 30 different IgG and IgA AMPA reactivities to modified antigens by ELISA and autoantigen arrays, in N=1985 newly diagnosed RA patients and population controls. The study utilized both previously established (i.e IgG and IgA CCP2; IgG ACPA fine-specificities; IgG anti-Carb fibrinogen and Carb FCS; IgG and IgA Cit/Carb/KAc/Orn(Ac)-vimentin), and novel assays (e.g. IgG anti-MAA and IgG anti-acetylated histones). Association with patient characteristics such as smoking and disease activity were explored. The newly developed assays were also evaluated in SLE disease controls and CCP2+ RA-risk individuals without arthritis.Results:Carb and KAc reactivities by different assays were primarily seen in patients also positive for citrulline-reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG acetylation reactivity was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone 2B reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles.Conclusion:We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Anti-Carb and anti-KAc could be considered reactivities within the “Cit-umbrella” similar to ACPA fine-specificities, while MAA is distinctly different.References:[1]Sahlström P, Hansson M, Steen J, Amara K, Titcombe PJ, Forsström B, Stålesen R, Israelsson L, Piccoli L, Lundberg K, Klareskog L, Mueller DL, Catrina AI, Skriner K, Malmström V, Grönwall C. Different Hierarchies of Anti-Modified Protein Autoantibody Reactivities in Rheumatoid Arthritis. Arthritis Rheumatol. 2020 Oct;72(10):1643-1657. PMID: 32501655Caroline Grönwall: None declared, Lisa Liljefors: None declared, Holger Bang Employee of: Employee at ORGENTEC Diagnostika GmbH, Aase Hensvold: None declared, Monika Hansson: None declared, Linda Mathsson-Alm Employee of: Employee at Thermo Fisher Scientific, Lena Israelsson: None declared, Anna Svärd: None declared, Cyril CLAVEL: None declared, Elisabet Svenungsson: None declared, Iva Gunnarsson: None declared, Guy Serre: None declared, Saedis Saevarsdottir: None declared, Alf Kastbom: None declared, Lars Alfredsson: None declared, Vivianne Malmström: None declared, Johan Rönnelid: None declared, Anca Catrina: None declared, Karin Lundberg: None declared, Lars Klareskog: None declared
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