| 1. |
- Saevarsdottir, S., et al.
(author)
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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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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Journal article (peer-reviewed)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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| 2. |
- Aoun, M., et al.
(author)
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Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
- 2023
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In: Journal of Experimental Medicine. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 0022-1007 .- 1540-9538. ; 220:11
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Journal article (peer-reviewed)abstract
- B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.
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| 3. |
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| 4. |
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| 5. |
- 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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| 8. |
- Barbulescu, A, et al.
(author)
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COMPARATIVE EFFECTIVENESS OF JAKI VERSUS BDMARDS; A NATIONWIDE STUDY IN RA
- 2021
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 68-68
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Conference paper (other academic/artistic)abstract
- The Janus kinase inhibitors (JAKi) have been increasingly used for the treatment of rheumatoid arthritis (RA) in Sweden, with baricitinib representing ~80% of prescriptions. Evidence regarding the comparative effectiveness of JAKis versus biologics (bDMARDs), and in particular non- tumour-necrosis-factor inhibitor (TNFi) bDMARDs, in real-life is limited.Objectives:To compare RA patients treated with bDMARDs and JAKi in Sweden, in terms of: (1) patient characteristics at treatment start; (2) proportions of patients remaining on therapy, and response rates, at 12 months.Methods:RA patients starting treatment in 2017 and 2018 with either a TNFi, rituximab, abatacept, interleukin 6 inhibitors (IL6i) or a JAKi as different lines of treatment were identified in the Swedish Rheumatology Quality Register. One patient could contribute with more than one treatment episode.Treatment response at 12 months was measured as EULAR good response, HAQ improvement >0.2 units, DAS28 and CDAI remission, and as 0 tender and swollen joint counts (28JC). Patients were classified as non-responders if they stopped treatment before evaluation due to safety or inefficacy. Responses for patients who stopped treatment due to pregnancy or death and patients on treatment but with missing response were imputed using multiple imputation.Proportions of responders and differences in proportions between treatment groups, adjusted using inverse probability of treatment weighting, were estimated using linear regression with robust standard errors.Results:JAKi were often used after bDMARDs, and less frequently prescribed in combination with methotrexate. Measured comorbidities were less frequent among JAKi initiators than among non-TNFi biologic initiators, but RA activity was similar (Table).Table 1.Patient characteristics at treatment initiationCharacteristicMedian (IQR) or N (%)AbataceptIL6iRituximabTNFiJAKiTreatment Starts6945346923497905Age63 (53-71)59 (48-70)65 (54-73)59 (47-68)60 (51-70)Female543 (78)441 (83)519 (75)2739 (78)759 (84)RA duration (years)13 (5-21)10 (5-18)12 (6-22)9 (3-17)13 (7-22)Rheum. factor535 (79)385 (73)588 (87)2405 (70)686 (77)DAS284.8 (3.9-5.6)4.9 (4.0-5.7)4.7 (3.8-5.5)4.4 (3.4-5.3)4.7 (3.9-5.7)HAQ1.3 (0.8-1.6)1.3 (0.8-1.8)1.3 (0.8-1.8)1.0 (0.5-1.4)1.3 (0.8-1.8)Tender joints5 (2-9)6 (3-10)5 (2-9)4 (2-8)6 (2-10)Swollen joints4 (2-6)4 (2-7)4 (2-7)3 (1-6)4 (2-7)ts/bDMARD line3 (2-4)3 (2-4)2 (1-4)1 (1-2)4 (2-6)At least one prev. TNFi539 (78)442 (83)457 (66)1448 (41)770 (85)At least one prev. non-TNFi271 (39)220 (41)243 (35)441 (13)584 (65)Methotrexate co-treatment264 (50)172 (40)286 (53)1708 (62)296 (40)Glucocorticoids co-treatment247 (47)186 (43)275 (51)1126 (41)389 (53)Cancer*90 (2.8)64 (2.3)363 (7.7)410 (1.8)20 (2.2)Cardio-vascular dis.*245 (7.5)123 (4.4)322 (6.8)749 (3.4)41 (4.4)Chronic respiratory dis.*303 (9.3)140 (5.0)473 (10.0)721 (3.2)50 (5.4)Diabetes*324 (9.9)216 (7.7)456 (9.7)1479 (6.7)69 (7.5)* any diagnosis within 5 years before start Adjusted differences in proportion with each response outcomeIn a crude comparison, 65% (61%-68%) of JAKi, 62% (59%-66%) of abatacept, 58% (53%-62%) of IL6i, 80% (77%-83%) of rituximab and 68% (67%-70%) of TNFi initiators remained on treatment at 12 months after start. Also, JAKi showed lower overall responder proportions than TNFi, rituximab and IL6i.After adjustment for demographic and socio-economic factors, RA disease activity, previous use of ts/bDMARDs, co-medication with glucocorticoids and methotrexate and comorbidities at baseline, no significant differences in responder proportions between JAKi and bDMARDs remained (Figure). Furthermore, the adjusted proportions of patients on treatment were higher for JAKi and rituximab than for the other bDMARDs.Conclusion:This preliminary analysis of patients treated in clinical practice found no statistically significant difference in effectiveness between JAKi and bDMARDs.Disclosure of Interests:Andrei Barbulescu: None declared, Johan Askling Grant/research support from: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. These entities have entered into agreements with Karolinska Institutet with JA as principal investigator, mainly in the context of safety monitoring of biologics via the ARTIS national safety monitoring system, Katerina Chatzidionysiou Speakers bureau: Eli Lilly, Abbvie and Pfizer, Consultant of: Eli Lilly, Abbvie and Pfizer, Helena Forsblad-d’Elia: None declared, Alf Kastbom Employee of: Sanofi, Ulf Lindström: None declared, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Grant/research support from: Bristol-Myers Squibb, Thomas Frisell: None declared
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| 9. |
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| 10. |
- Lonnblom, E, et al.
(author)
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AUTOANTIBODIES TO JOINT PROTEINS AS NOVEL BIOMARKERS FOR THE DIAGNOSIS OF UNTREATED EARLY RHEUMATOID ARTHRITIS
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 546-546
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Conference paper (other academic/artistic)abstract
- Autoantibodies to citrullinated protein (ACPA; measured as anti-CCP; aCCP) and rheumatoid factor (RF) appear years before clinical onset of RA and are essential tools in today’s classification criteria for RA. In animal models, antibodies to joint specific proteins (JP) can induce arthritis, and they are also present at onset of RA [1]. As there is a need for increased precision for early diagnosis of RA as well as identification of different subtypes of the disease, we aim to assess whether autoantibodies to native or modified JP can be used for early and precise diagnosis of RA.ObjectivesTo study whether antibodies to JP, alone or in combination with ACPA/RF, could increase the diagnostic sensitivity and specificity in untreated early (ue)RA patients.MethodsAntibodies to JP were analysed in serum from patients in three independent ueRA cohorts as well as from population controls without rheumatic diseases (WINGA, Gothenburg and MFM-ÅUS, Malmö n=1062). ERAp (n=66), the smallest and most recent cohort was chosen for screening, and BARFOT and TIRA-2 (n=1939) for validation. We have developed a bead-based multianalyte flow immunoassay [2] and screened approx. 350 peptides derived from JPs of interest. We included monoclonal antibodies as assay calibrators and determined limit of detection (LoD). To assess positivity for autoantibodies to JP of interest above LoD, we used 5MAD (median absolute deviation) of the control populations as the cut-off.ResultsIn the ERAp cohort, 5 autoantibodies discriminated RA patients from controls with 81% sensitivity and 100% specificity (Table 1). The same autoantibodies had 68% sensitivity and 98% specificity in the combined BARFOT and TIRA-2 cohorts. Together with RF and aCCP, only 2 of the 5 autoantibodies added statistically significant diagnostic value, increasing the sensitivity from 48% to 61% with 99% specificity. In aCCP- and RF-negative ueRA patients (n=536), the novel biomarkers identified 22.5% of the patients with 99% specificity compared to controls.Table 1.Diagnostic capacity of the joint-specific antibodiesTest panelPerformanceGroup of patientsaCCP+RF+JP+SensitivitySpecificityAUC(ROC)ERApAll patients (n=66)--X81%100%89%RF and aCCP-neg patients (n=7)1------BARFOT and TIRA-2, combined dataAll patients (N=1939)--X68%98%86%All patients (N=1939)X--58%99%78%All patients (N=1939)2XX-48%100%84%All patients (N=1939)2, 3XXX61%99%86%RF and/or aCCP-pos patients (N=1403)--X84%99%93%RF and aCCP-neg patients (N=536)--X22%99%67%RA, literature valuesAnti-CCP testXN/AN/A53–71%95–96%N/A1Not analysed due to lack of power2This patient population is both aCCP+ and RF+3Only 2 of the 5 autoantibodies added statistically significant to the diagnostic valueAUC, Area under the curve; ROC, receiver operating characteristic curve; N/A, not applicable. Controls without rheumatic diseases: N=935 for BARFOT / TIRA-2 and N=27 for ERAp.ConclusionAutoantibodies to JP discriminate ueRA patients better then aCCP and RF alone and add an increased diagnostic value in particular for seronegative patients.References[1]Holmdahl, R., V. Malmstrom, and H. Burkhardt, Autoimmune priming, tissue attack and chronic inflammation - the three stages of rheumatoid arthritis. Eur J Immunol, 2014. 44(6): p. 1593-9.[2]Viljanen, J., et al., Synthesis of an Array of Triple-Helical Peptides from Type II Collagen for Multiplex Analysis of Autoantibodies in Rheumatoid Arthritis. ACS Chem Biol, 2020. 15(9): p. 2605-2615. Correction: ACS Chem Biol, 2020. 15(11): p. 3072AcknowledgementsBARFOT study group.Disclosure of InterestsErik Lönnblom: None declared, Monica Leu Agelii: None declared, Outi Sareila Employee of: Part time employee in Vacara AB, Ingiäld Hafström: None declared, Maria Andersson: None declared, Lei Cheng: None declared, Göran Bergström: None declared, Anna-Karin H Ekwall: None declared, Anna Rudin: None declared, Alf Kastbom: None declared, Christopher Sjowall: None declared, Bingze Xu: None declared, Lennart T.H. Jacobsson: None declared, Johan Viljanen: None declared, Jan Kihlberg: None declared, Inger Gjertsson: None declared, Rikard Holmdahl Shareholder of: Rikard Holmdahl the founder of Vacara AB.
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| 11. |
- Ziegelasch, Michael, et al.
(author)
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Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus : results from two well-defined European cohorts.
- 2016
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In: Arthritis Research & Therapy. - : BioMed Central. - 1478-6362. ; 18:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data.METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available.RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients.CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.
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| 12. |
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| 13. |
- Barbulescu, A., et al.
(author)
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Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data
- 2022
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In: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:10, s. 3952-3962
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Journal article (peer-reviewed)abstract
- Objectives To describe the use of baricitinib and tofacitinib by Swedish RA patients and to compare their effectiveness with that of biologic DMARDs (bDMARDs). Methods RA patients who initiated baricitinib (n = 1420), tofacitinib (n = 316), abatacept (n = 1050), IL-6 inhibitors (IL-6is; n = 849), rituximab (n = 1101) or TNF inhibitors (TNFis; n = 6036) between January 2017 and November 2019 were followed for a minimum of 1 year using data from several linked Swedish national registers. Proportions reaching a good EULAR 28-joint DAS (DAS28) response, HAQ Disability Index (HAQ-DI) improvement >0.2 units and Clinical Disease Activity Index (CDAI) remission were compared at 1 year, imputing discontinued treatments as 'non-response'. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to 3 months after treatment initiation. Results On average, baricitinib, and particularly tofacitinib, were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted 1 year response proportions were consistently lower on TNFi compared with baricitinib, with differences of -4.3 percentage points (95% CI -8.7, 0.1) for good EULAR response, -9.9 (-14.4 to -5.4) for HAQ-DI improvement and -6.0 (-9.8 to -2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to 3 months supported the 1 year findings. Conclusions Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures.
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| 14. |
- Coenen, Marieke J H, et al.
(author)
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Genetic Variants in Toll-Like Receptors Are Not Associated with Rheumatoid Arthritis Susceptibility or Anti-Tumour Necrosis Factor Treatment Outcome
- 2010
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:12
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Journal article (peer-reviewed)abstract
- Background: Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication. Methodology and Principal Findings: 22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. Conclusion: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.
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| 15. |
- Dubovyk, Violetta, et al.
(author)
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Obesity is a risk factor for poor response to treatment in early rheumatoid arthritis: a NORD-STAR study
- 2024
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In: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 10:2
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Journal article (peer-reviewed)abstract
- Objective This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA). Methods This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI >= 30 kg/m(2). All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI. Results Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms. Conclusion In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received.
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| 16. |
- Eloff, Emma, et al.
(author)
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Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain
- 2021
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In: Scandinavian Journal of Rheumatology. - : Taylor & Francis Group. - 0300-9742 .- 1502-7732. ; 50:3, s. 189-197
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Journal article (peer-reviewed)abstract
- Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57–81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1–4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000–1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7–11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose–response relationship between RA-related autoantibodies and risk of arthritis development.
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| 17. |
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| 18. |
- Frisell, Thomas, et al.
(author)
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Comparative effectiveness of abatacept, rituximab, tocilizumab and TNFi biologics in RA : Results from the nationwide Swedish register
- 2019
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In: Rheumatology (United Kingdom). - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 58:8, s. 1367-1377
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Journal article (peer-reviewed)abstract
- Objectives: Current guidelines rank abatacept, rituximab, tocilizumab and TNF-inhibitors (TNFi) as having equal effectiveness for the treatment of RA, at least as second line therapies. These recommendations are mainly based on meta-analysis of randomized controlled trials, with few direct drug-drug comparisons. Our objective was to compare the real-world absolute and relative effectiveness among RA patients starting any of the available biologic DMARDs (bDMARDs). Methods: We used the Swedish Rheumatology Register to identify patients with RA initiating TNFi, rituximab, abatacept or tocilizumab in 2010-2016 as first bDMARD (n = 9333), or after switch from TNFi as first bDMARD (n = 3941). National Swedish registers provided additional covariates and censoring events. Effectiveness was assessed 3 and 12 months after treatment start, as the proportion remaining on therapy and with EULAR Good Response, HAQ improvement >0.2, zero swollen/tender joints and CDAI remission. Adjusted differences were estimated with multivariable linear regression. Results: Patients starting non-TNFi (vs TNFi) as first bDMARD had a higher proportion remaining on drug and reaching most response outcomes as first bDMARD (1-year EULAR Good Response/HAQ improvement: TNFi 24.9/25.4%, rituximab 28.6/37.2%, abatacept 31.9/33.7%, tocilizumab 50.9/43.1%). After switch from a first TNFi, rituximab and tocilizumab, but not abatacept, were associated with significantly better response measures than TNFi (1-year EULAR Good Response/HAQ improvement: TNFi 11.6/16.1%, rituximab 24.8/33.2%, abatacept 13.1/17.5%, tocilizumab 34.1/29.4%). Differences remained significant after adjusting for potential confounders. Conclusion: Treatment outcomes among RA patients treated in Swedish clinical practice are in line with a superior effectiveness of non-TNFi bDMARDs, in particular tocilizumab and rituximab, compared with TNFi.
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| 19. |
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| 20. |
- Frodlund, Martina, et al.
(author)
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Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus : associations with disease phenotypes, vascular events and damage accrual
- 2018
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In: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 194:1, s. 27-38
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Journal article (peer-reviewed)abstract
- Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.
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| 21. |
- Ge, Changrong, et al.
(author)
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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
- 2019
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In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 210-221
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Journal article (peer-reviewed)abstract
- Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.
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| 22. |
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| 23. |
- Kastbom, Åsa A., et al.
(author)
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Parents? : Observations and Reports on the Sexual Behaviour of 7 to 13 Years Old Children
- 2012
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In: Reproductive System & Sexual Disorders. - : OMICS International. - 2161-038X. ; 1:2, s. 2-7
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Journal article (peer-reviewed)abstract
- Aim: To investigate sexual behaviours, types and frequencies, among Swedish children in the age group of 7-13 years, as observed and reported by their parents and to give professionals in different areas a greater knowledge of sexual behaviour among younger school children.Methods: The parents of 418 children answered questionnaires about their child's behaviour, both general and sexual, and about their own attitudes.Results: We found that most sexual behaviours we asked about were reported by the parents as common, and are in part related to, or vary with, age and gender. A small number of sexual behaviours often referred to as problematic behaviour were found to be very unusual in this normative group of Swedish children.Conclusion: Behaviours usually referred to as sexualized and problematic were rare in this normative sample of children at 7-13 years of age. The results are of importance for clinicians' evaluation of sexual behaviours reported by parents.
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| 24. |
- Kastbom, Åsa A., 1971-
(author)
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Sexual behaviour, debut and identity among Swedish Schoolchildren
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Background: Sexual behaviour among schoolchildren and adolescents is a sparsely researched area and there are delicate methodological obstacles and ethical concerns when conducting such research. Still it is a subject that engages both parents and professionals. A sexualized behaviour or an early sexual debut (younger than 14 years) can be a sign of sexual abuse. It is therefore of importance to describe what is common and what is uncommon sexual behaviour among children and what the consequences of an early or a late sexual debut may be for the individual upon reaching late adolescence. Adolescents who identify themselves as lesbian, gay or bisexual (LGB) are also a group that needs further attention and research since they are often described as having a lower quality of life and more often experience child abuse than heterosexual teens.Aims: The research leading to this thesis had four goals: 1) to elucidate the sexual behaviour of children between the ages of 7 and 13 as observed by their parents, 2) to investigate the relationship between an early sexual debut (before 14 years of age) and socio-demographic data, sexual experience, health, experience of child abuse and behaviour at 18-years-of-age, 3) to explore associations with no sexual debut (no oral, vaginal or anal sex) at the age of 18, and 4) to describe the relationship between sexual identification and socio-demographic background data, sexual behaviour, health and health behaviour, experiences of child sexual and/or physical abuse and present behaviour among Swedish adolescents.Methods: The parents of 418 children answered questionnaires about their child’s behaviour, both general and sexual, and a sample of 3432 Swedish high school students completed a survey about sexuality, health and abuse at the age of 18. In addition, 362 members of the Swedish Federation for Lesbian, Gay, Bisexual and Transgender Rights (RFSL) completed the same survey at a mean age of 21.4 years.Results: Most of the sexual behaviours among the schoolchildren were common, and in part related to, or varied with, age and gender. A small number of sexual behaviours often referred to as sexualised or problematic behaviours (for example, kissing adults with the tongue, imitating intercourse, masturbating in public, and touching other children’s genitals with the mouth) were found to be very unusual or not reported by any parent in this normative group of Swedish children. Among the adolescents, an early debut (younger than 14 years of age) correlated positively with number of partners, experience of oral and anal sex, smoking, drug and alcohol use and antisocial behaviour, such as being violent, lying, stealing and running away from home. Girls with an early sexual debut had significantly more experience of sexual abuse while boys with an early sexual debut were more likely to have a weak sense of coherence, low self-esteem and poor mental health, together with experience of sexual abuse, selling sex and physical abuse. A multiple logistic regression model showed that a number of antisocial acts and health behaviours remained significant, but early sexual debut did not increase the risk of psychiatric symptoms, low self-esteem or low sense of coherence at 18-years-of-age. Just under a quarter (24.6%) of the 3,380 adolescents had not had their sexual debut (no oral, anal or vaginal sex by the age of 18). There was a positive correlation between not debuting sexually at age 18 and a number of factors such as: being more likely to have caring fathers; parents born outside Europe; low sexual desire; lower pornography consumption; lower alcohol and tobacco consumption; less antisocial behavior and fewer experiences of sexual abuse than 18 year olds who had already made their sexua debut. Adolescents with a minority sexual identity more often described their relationship with their parents as based on low care and high overprotection than did their heterosexual peers. The minority adolescents used alcohol and drugs to a significantly higher degree than the heterosexual adolescents. Multivariate analysis showed a positive correlation between a minority sexual identity and experience of anal sex, higher sexual lust, experience of sexual abuse, physical abuse and sexual exploitation. It was more than twice as common to have experience of penetrating sexual abuse and physical abuse with a sexual minority identity.Conclusions: Behaviours usually referred to as sexualised and problematic are uncommon among children at 7-13 years of age. Professionals and should give a child showing a sexualised behaviour special attention and investigate the reasons for the behaviour. Early sexual debut seems to be associated with problematic behaviours during later adolescence, indicating the fact that the early debut for some children is associated with an increased vulnerability, which has to be addressed. Family socio-demographics such as family stability and/or cultural status matter when it comes to time of sexual debut. Personality also seems to matter and further studies are needed to investigate if there is any correlation between personality traits and late sexual debut. Adolescents with no sexual debut at 18 years of age reported fewer antisocial acts, were less likely to smoke and drink alcohol, had less sexual desire and less experience of sexual abuse. Young people with a sexual minority identity (homo- and bisexual) could be seen to have a lower quality of life compared to heterosexual peers and studies need to be done to further explore possible reasons. They have a higher risk of having experience of sexual and physical abuse compared to heterosexual adolescents. Professionals need to be more aware of this group’s additional vulnerability including the increased risk of child abuse and offer different forms of support.
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| 25. |
- Li, T. T., et al.
(author)
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Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage
- 2023
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82:6, s. 799-808
-
Journal article (peer-reviewed)abstract
- ObjectivesTo identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA). MethodsIgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining. ResultsPeptide GPI(293-307) was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI(293-307) epitopes, and high affinity anti-GPI(293-307) IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI(293-307) IgG antibodies induced arthritis in mice. Moreover, anti-GPI(293-307) IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI(293-307)-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI(293-307) antibodies. ConclusionsWe have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.
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| 26. |
- Nilsson, Lena, et al.
(author)
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Association between vaccination and preventive routines on COVID-19-related mortality in nursing home facilities : a population-based systematic retrospective chart review
- 2022
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In: Primary Health Care Research and Development. - : Cambridge University Press. - 1463-4236 .- 1477-1128. ; 23
-
Research review (peer-reviewed)abstract
- Background:Older and frail individuals are at high risk of dying from COVID-19, and residents in nursing homes (NHs) are overrepresented in death rates. We explored four different periods during the COVID-19 pandemic to analyze the effects of improved preventive routines and vaccinations, respectively, on mortality in NHs. Methods:We undertook a population-based systematic retrospective chart review comprising 136 NH facilities in southeast Sweden. All residents, among these facilities, who died within 30 days after a laboratory-verified COVID-19 diagnosis during four separate 92-day periods representing early pandemic (second quarter 2020), middle of the pandemic (fourth quarter 2020), early post-vaccination phase (first quarter 2021), and the following post-vaccination phase (second quarter 2021). Mortality together with electronic chart data on demographic variables, comorbidity, frailty, and cause of death was collected. Results:The number of deaths during the four periods was 104, 120, 34 and 4, respectively, with a significant reduction in the two post-vaccination periods (P < 0.001). COVID-19 was assessed as the dominant cause of death in 20 (19%), 19 (16%), 4 (12%) and 1 (3%) residents in each period (P < 0.01). The respective median age in the four studied periods varied between 87and 89 years, and three or more diagnoses besides COVID-19 were present in 70-90% of the respective periods study population. Considerable or severe frailty was found in all residents. Conclusions:Vaccination against COVID-19 seems associated with a reduced number of deaths in NHs. We could not demonstrate an effect on mortality merely from the protective routines that were undertaken.
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| 27. |
- Ostergaard, Mikkel, et al.
(author)
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Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis : 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial
- 2023
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In: Annals of the Rheumatic Diseases. - : BMJ PUBLISHING GROUP. - 0003-4967 .- 1468-2060. ; 82:10, s. 1286-1295
-
Journal article (peer-reviewed)abstract
- Background The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. Methods Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naive early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI <= 2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). Results Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences. Conclusions Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments.
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| 28. |
- Perini, Irene, 1983-, et al.
(author)
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Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation
- 2023
-
In: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; :6, s. 2563-2571
-
Journal article (peer-reviewed)abstract
- Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.
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| 29. |
- Stuemer, J., et al.
(author)
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Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy
- 2017
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In: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 189:3, s. 372-382
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Journal article (peer-reviewed)abstract
- The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.
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| 30. |
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| 31. |
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| 32. |
- Van Hoovels, L., et al.
(author)
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IgA rheumatoid factor in rheumatoid arthritis
- 2022
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In: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 60:10, s. 1617-1626
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Journal article (peer-reviewed)abstract
- Objectives Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context. Methods An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available. Results The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjogren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies. Conclusions IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.
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| 33. |
- Van Hoovels, L., et al.
(author)
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Multicentre study to improve clinical interpretation of rheumatoid factor and anti-citrullinated protein/peptide antibodies test results
- 2022
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In: RMD Open. - : BMJ. - 2056-5933. ; 8:1
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) are important biomarkers for diagnosis of rheumatoid arthritis (RA). However, there is poor harmonisation of RF and ACPA assays. The aim of this study was to refine RF and ACPA interpretation across commercial assays. MATERIALS AND METHODS: Six total RF isotype-non-specific assays, 3 RF IgM isotype-specific assays and 9 ACPA immunoglobulin G assays of 13 different companies were evaluated using 398 diagnostic samples from patients with RA and 1073 disease controls. RESULTS: Using cut-offs proposed by the manufacturer, there was a large variability in diagnostic sensitivity and specificity between assays. Thresholds of antibody levels were determined based on predefined specificities and used to define test result intervals. Test result interval-specific likelihood ratios (LRs) were concordant across the different RF and ACPA assays. For all assays, the LR for RA increased with increasing antibody level. Higher LRs were found for ACPA than for RF. ACPA levels associated with LRs >80 were found in a substantial fraction (>22%) of patients with RA. CONCLUSION: Defining thresholds for antibody levels and assigning test result interval-specific LRs allows alignment of clinical interpretation for all RF and ACPA assays. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 34. |
- Van Hoovels, L., et al.
(author)
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Standardisation of ACPA tests: evaluation of a new candidate reference preparation
- 2022
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:10, s. 1379-1384
-
Journal article (peer-reviewed)abstract
- Introduction Commercial assays measuring antibodies to citrullinated protein/peptide (ACPA) show poor quantitative agreement. The diagnostic industry has never adopted the International Union of Immunological Societies-Centers for Disease Control and Prevention (IUIS-CDC) ACPA reference standard. Recently, the National Institute for Biological Standards and Control (NIBSC) prepared a new candidate ACPA standard (18/204). We evaluated both reference materials using different commercially available ACPA assays. Materials and methods This is an international study in which the NIBSC candidate ACPA standard and the IUIS-CDC ACPA reference material were analysed together with 398 diagnostic samples from individuals with rheumatoid arthritis (RA) and in 1073 individuals who did not have RA using nine commercial ACPA assays. Results For both reference materials and samples from individuals with RA and individuals who did not have RA, there were large differences in quantitative ACPA results between assays. For most assays, values for the IUIS-CDC standard were lower than values for NIBSC 18/204 and the IUIS-CDC/NIBSC ratio was comparable for several, but not all assays. When NIBSC 18/204 was used as a calibrator, an improvement in alignment of ACPA results across several of the evaluated assays was obtained. Moreover, NIBSC 18/204 could align clinical interpretation for some but not all assays. Conclusion Adoption of an international standard for ACPA determination is highly desirable. The candidate NIBSC 18/204 standard improved the standardisation and alignment of most ACPA assays and might therefore be recommended to be used as reference in commercial assays.
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| 35. |
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| 36. |
- Wang, Yan, et al.
(author)
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Rheumatoid arthritis patients display B-cell dysregulation already in the naive repertoire consistent with defects in B-cell tolerance
- 2019
-
In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
-
Journal article (peer-reviewed)abstract
- B cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA(+) RA compared to healthy controls, including an increase in HLA-DR across subsets, CD22 in clusters of IgM(+) B cells and CD11c in IgA(+) memory. Moreover, both IgA(+) and IgG(+) double negative (IgD(-) CD27(-)) CD11c(+) B cells were increased in ACPA+ RA, and there was a trend for elevation in a CXCR5/CCR6(high) transitional B-cell cluster. In the RA BCR repertoire, there were significant differences in subclass distribution and, notably, the frequency of VH with low somatic hypermutation (SHM) was strikingly higher, especially in IgG1 (p amp;lt; 0.0001). Furthermore, both ACPA(+) and ACPA(-) RA patients had significantly higher total serum IgA and IgM compared to controls, based on serology of larger cohorts (n = 3494 IgA; n = 397 IgM). The observed elevated Ig-levels, distortion in IgM(+) B cells, increase in double negative B cells, change in B-cell markers, and elevation of unmutated IgG(+) B cells suggests defects in B-cell tolerance in RA. This may represent an underlying cause of increased polyreactivity and autoimmunity in RA.
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| 37. |
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| 38. |
- 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
-
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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