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Idborg, H., Zandian, A., Ossipova, E., Wigren, E., Preger, C., Mobarrez, F., . . . Jakobsson, P.-J. (2019). Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.. Frontiers in Immunology, 10, Article ID 1029.
Open this publication in new window or tab >>Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed) Published
Abstract [en]

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10-9, 3 × 10-6, and 5 × 10-6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

Keywords
Interferon regulating factor 5 (IRF5), SLE - Systemic Lupus Erythematous, antibody suspension bead arrays, biomarker discovery, hierarchical clustering, plasma proteomics, subgroups, unsupervised clustering
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-385062 (URN)10.3389/fimmu.2019.01029 (DOI)000468162000001 ()31156624 (PubMedID)
Funder
Swedish Research Council, 2017-02577Swedish Research Council, 2018-02399Swedish Research Council, 2018-02535Swedish Research Council, 2018-02000Stockholm County Council, 20160378Stockholm County Council, 20170038Swedish Rheumatism Association, R-748261Swedish Rheumatism Association, R-755861Swedish Rheumatism Association, R-753741Swedish Rheumatism Association, R-850611Swedish Rheumatism Association, R-739631Swedish Society of Medicine
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-11Bibliographically approved
Phuong, T. N., Ngoc, L. N., Xuan, H. N., Rönnelid, J., Padyukov, L. & Lundberg, I. E. (2019). Clinical phenotype, autoantibody profile and HLA-DR-type in Vietnamese patients with idiopathic inflammatory myopathies [Letter to the editor]. Rheumatology, 58(2), 361-363
Open this publication in new window or tab >>Clinical phenotype, autoantibody profile and HLA-DR-type in Vietnamese patients with idiopathic inflammatory myopathies
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2019 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 58, no 2, p. 361-363Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-379424 (URN)10.1093/rheumatology/key313 (DOI)000459631600027 ()30371850 (PubMedID)
Funder
Swedish Research Council, K2014-52X-14045-14
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Espinosa-Ortega, F., Holmqvist, M., Alexanderson, H., Storfors, H., Mimori, T., Lundberg, I. E. & Rönnelid, J. (2019). Comparison of autoantibody specificities tested by a line blot assay and immunoprecipitation-based algorithm in patients with idiopathic inflammatory myopathies [Letter to the editor]. Annals of the Rheumatic Diseases, 78(6), 858-860
Open this publication in new window or tab >>Comparison of autoantibody specificities tested by a line blot assay and immunoprecipitation-based algorithm in patients with idiopathic inflammatory myopathies
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 6, p. 858-860Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-389919 (URN)10.1136/annrheumdis-2018-214690 (DOI)000471072800041 ()30760469 (PubMedID)
Funder
Swedish Research CouncilKing Gustaf V Jubilee Fund
Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2019-08-02Bibliographically approved
Lloyd, K. A., Wigerblad, G., Sahlstrom, P., Garimella, M. G., Chemin, K., Steen, J., . . . Gronwall, C. (2019). Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis. Frontiers in Immunology, 9, 1-22, Article ID 3033.
Open this publication in new window or tab >>Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, p. 1-22, article id 3033Article in journal (Refereed) Published
Abstract [en]

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein autoantibody (AMPA) profile of the ACPA was found to correlate with the functional activity of the antibodies. In conclusion, when investigating monoclonal ACPA, we could group ACPA into distinct subsets based on their nuclear binding-patterns and acetylation-mediated binding to apoptotic cells, neutrophils, and NETs. Differential anti-modified protein reactivities of RA-autoantibody subsets could have an important functional impact and provide insights in RA pathogenesis.

Keywords
anti-citrullinated protein autoantibodies, acetylation, rheumatoid arthritis, anti-CCP, PAD4, apoptosis, neutrophil extracellular traps (NETs), ANA
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-374429 (URN)10.3389/fimmu.2018.03033 (DOI)000454910500001 ()30662440 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism Association
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
ElShafie, A. I., Elbagir, S., Aledrissy, M. I. E., Elagib, E. M., Nur, M. A. M. & Rönnelid, J. (2019). Occurrence of anti-CCP2 and RF isotypes and their relation to age and disease severity among Sudanese patients with rheumatoid arthritis. Clinical Rheumatology, 38(6), 1545-1553
Open this publication in new window or tab >>Occurrence of anti-CCP2 and RF isotypes and their relation to age and disease severity among Sudanese patients with rheumatoid arthritis
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2019 (English)In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 38, no 6, p. 1545-1553Article in journal (Refereed) Published
Abstract [en]

Objective Anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2) and rheumatoid factor (RF) in rheumatoid arthritis (RA) has been extensively assessed in industrialized countries. We investigated the diagnostic and prognostic impact of anti-CCP2 and RF isotypes in a Sudanese cross-sectional RA cohort. Methods Consecutive RA patients (n=281) diagnosed according to the 1987 ACR criteria were included 2008-2010. Anti-CCP2 and RF isotypes (IgA, IgM, and IgG) were measured by enzyme immunoassay in 262 patients, with reference intervals aligned to the same diagnostic specificity as for anti-CCP2 (97.6%) using national controls. Results IgA RF was the predominant RA-associated autoantibody (56%), followed by IgM RF and anti-CCP2 (both 52%) and IgG RF (49%). In receiver operator characteristic analysis, IgA RF also showed the largest area under the curve. Patients with IgG RF were younger and had 8years lower median age of disease onset compared to antibody negative patients (p<0.0001). IgG RF was the only marker associated with a high number of involved joints (p=0.028), and together with anti-CCP2 were the strongest markers for finger deformities (p=0.016 and p=0.012), respectively. No statistical differences were found for disease duration, ESR and Hb levels, and occurrence of erosions/osteopenia for any of the investigated autoantibodies. Conclusion Whereas IgA RF showed the best diagnostic performance, IgG RF associated with low age of RA onset, high number of involved joints, and finger deformities. These findings indicate that RA-associated antibodies other than conventional IgM RF and anti-CCP2 might be informative in non-Caucasian RA populations.

Place, publisher, year, edition, pages
SPRINGER LONDON LTD, 2019
Keywords
Anti-citrullinated protein antibodies, Eastern Africa, Rheumatoid arthritis, Rheumatoid factor, Sudan
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-387936 (URN)10.1007/s10067-019-04431-6 (DOI)000469866000002 ()30656490 (PubMedID)
Funder
Swedish Research Council, K2014-68X-20611-07-3
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Tjärnlund, A., Lundberg, I. E. & Rönnelid, J. (2019). Response to: 'Detection of myositis-specific antibodies: additional notes' by Infantino et al [Letter to the editor]. Annals of the Rheumatic Diseases, 78(4), Article ID e30.
Open this publication in new window or tab >>Response to: 'Detection of myositis-specific antibodies: additional notes' by Infantino et al
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 4, article id e30Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-389925 (URN)10.1136/annrheumdis-2018-213341 (DOI)000471064600008 ()29615410 (PubMedID)
Available from: 2019-08-01 Created: 2019-08-01 Last updated: 2019-08-01Bibliographically approved
Tjärnlund, A., Rönnelid, J., Bottai, M. & Lundberg, I. E. (2019). Response to: ‘Detection of myositis-specific antibodies’ by Vulsteke et al [Letter to the editor]. Annals of the Rheumatic Diseases, 78(1), Article ID UNSP e8.
Open this publication in new window or tab >>Response to: ‘Detection of myositis-specific antibodies’ by Vulsteke et al
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 1, article id UNSP e8Article in journal, Letter (Other academic) Published
Keywords
autoantibodies, disease activity, inflammation
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-343353 (URN)10.1136/annrheumdis-2018-212948 (DOI)000455953500008 ()29382639 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2019-02-05Bibliographically approved
Idborg, H., Zandian, A., Sandberg, A.-S., Nilsson, B., Elvin, K., Truedsson, L., . . . Jakobsson, P.-J. (2019). Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjogren's syndrome differ in molecular signatures and treatment perspectives. Arthritis Research & Therapy, 21, Article ID 62.
Open this publication in new window or tab >>Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjogren's syndrome differ in molecular signatures and treatment perspectives
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2019 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, article id 62Article in journal (Refereed) Published
Abstract [en]

Background: Previous studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers.

Methods: In a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients’ autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjögren’s syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups.

Results: The aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve = 0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, α-1 antitrypsin, neutrophils, and triglycerides).

Conclusions: Our observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments.

Keywords
Systemic lupus erythematosus, Antiphospholipid syndrome, Sjogren's syndrome, Personalized medicine, Affinity-based proteomics, Subgroups
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-378991 (URN)10.1186/s13075-019-1836-8 (DOI)000459147000001 ()30777133 (PubMedID)
Funder
Swedish Research Council, 2017-02577Swedish Research Council, 2014-33867VinnovaAstraZenecaSwedish Heart Lung FoundationStockholm County Council, 20160378; 20170038The King Gustaf V's Jubilee FoundationSwedish Rheumatism Association, R-755861; R-73931Åke Wiberg FoundationSwedish Society of Medicine
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Meroni, P. L., Chan, E. K., Damoiseaux, J., Coelho Andrade, L. E., Bossuyt, X., Conrad, K., . . . Fritzler, M. J. (2019). Unending story of the indirect immunofluorescence assay on HEp-2 cells: old problems and new solutions? [Letter to the editor]. Annals of the Rheumatic Diseases, 78(6), Article ID e46.
Open this publication in new window or tab >>Unending story of the indirect immunofluorescence assay on HEp-2 cells: old problems and new solutions?
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 6, article id e46Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-389920 (URN)10.1136/annrheumdis-2018-213440 (DOI)000471072800001 ()29666046 (PubMedID)
Available from: 2019-08-01 Created: 2019-08-01 Last updated: 2019-08-01Bibliographically approved
Tjärnlund, A., Tang, Q., Wick, C., Dastmalchi, M., Mann, H., Studynkova, J. T., . . . Lundberg, I. E. (2018). Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial. Annals of the Rheumatic Diseases, 77(1), 55-62
Open this publication in new window or tab >>Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 1, p. 55-62Article in journal (Refereed) Published
Abstract [en]

Objectives: To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM).

Methods: Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines.

Results: 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies.

Conclusions: In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3(+) Tregs suggests a positive effect of treatment in muscle tissue.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-338993 (URN)10.1136/annrheumdis-2017-211751 (DOI)000417778700013 ()28993346 (PubMedID)
Funder
Swedish Research Council, GRANTK2014-52X-14045-14-3Swedish Rheumatism AssociationStockholm County CouncilThe Karolinska Institutet's Research Foundation
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-27Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-1186-3226

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