| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Brink, M, et al.
(author)
-
PULMONARY FIBROSIS IN EARLY RHEUMATOID ARTHRITIS IN RELATION TO GENETIC LOCI AND INDIVIDUAL ACPA SPECIFICITIES
- 2022
-
In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 203-204
-
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
|
|
| 6. |
|
|
| 7. |
- Elbagir, S, et al.
(author)
-
ANTI-PHOSPHATIDYLSERINE/PROTHROMBIN ANTIBODIES AND VASCULAR EVENTS ASSOCIATE POSITIVELY WITH HLA-DRB1*13 AND NEGATIVELY WITH HLA-DRB1*03 IN SLE
- 2022
-
In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 658-659
-
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.
|
|
| 8. |
|
|
| 9. |
- Gronwall, C, et al.
(author)
-
THE RELATIONSHIP BETWEEN DIFFERENT IGG AND IGA ANTI-MODIFIED PROTEIN AUTOANTIBODIES IN RHEUMATOID ARTHRITIS
- 2021
-
In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 206-207
-
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
|
|
| 10. |
|
|
