| 1. |
- Gronwall, C, et al.
(författare)
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THE RELATIONSHIP BETWEEN DIFFERENT IGG AND IGA ANTI-MODIFIED PROTEIN AUTOANTIBODIES IN RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 206-207
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)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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| 2. |
- 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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| 3. |
- Mathsson-Alm, L, et al.
(författare)
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THE NORA PROJECT - PREDICTION OF THERAPY RESPONSE IN RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 1090-1090
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)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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