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- 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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- Brink, Mikael, et al.
(författare)
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Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides and Anti-Carbamylated Antibodies in Individuals Before the Onset of Rheumatoid Arthritis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.
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- 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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