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Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease
Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-6916-5490
Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
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2020 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 199, no 3, p. 245-254Article in journal (Refereed) Published
Abstract [en]

Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS (TM) Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjogrens syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2020. Vol. 199, no 3, p. 245-254
Keywords [en]
autoantibodies; autoimmunity; complement; human; systemic lupus erythematosus
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-164196DOI: 10.1111/cei.13402ISI: 000513952100007PubMedID: 31778219Scopus ID: 2-s2.0-85076720021OAI: oai:DiVA.org:liu-164196DiVA, id: diva2:1413970
Note

Funding Agencies|the Swedish Society of Medicine; Swedish Society of Medicine; the County Council of Ostergotland; Swedish Rheumatism Association; the Swedish Rheumatism Association; the King Gustaf V and Queen Victorias Freemasons foundation; the King Gustaf Vs 80-year Anniversary foundation

Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-04-07Bibliographically approved
In thesis
1. Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus
Open this publication in new window or tab >>Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) has an exceptionally heterogeneous clinical spectrum, ranging from mild disease limited to skin and joints to severe manifestations with renal disorder, central nervous system disease, severe cytopenias and thromboembolic events. Important clinical challenges include the prediction of disease flares and the identification of individuals that are likely to evolve severe disease with accrual of organ damage and worse prognosis. Autoantibodies, i.e. antinuclear antibodies (ANA) and antiphospholipid antibodies (aPL), and interferon alpha (IFN-α) that contribute to formation of immune complexes with nuclear antigens, are hallmarks considered to drive the disease in a vicious circle of antigen exposure, autoantibody production, inflammation and organ damage. There are few good biomarkers to predict severe SLE and organ damage. The aim of this PhD project was thus to increase the knowledge regarding ANA as well as aPL, and other potential biomarkers in relation to clinical features and disease outcomes in SLE.

As expected, we found that the homogeneous ANA staining pattern was most common, and that it was associated with the occurrence of the ‘immunological disorder’ criterion. Speckled ANA was the second most common staining pattern, and it was inversely associated with arthritis, the ‘immunological disorder’ criterion and organ damage (Paper I). We also demonstrated that a considerable proportion of the patients lost ANA-positivity over time, whereas consistent staining patterns were most frequent (Paper V).

Survival of patients with SLE has improved. Yet, in comparison to the general population, irreversible organ damage and increased mortality remains a critical concern. In Paper II, our cross-sectional analysis showed that more than a quarter of the patients had any aPL isotype (IgG, IgM or IgA class), and 14% were classified with antiphospholipid antibody syndrome (APS). A positive lupus anticoagulant (LA) test and/or IgG aPL tests were associated with most APS-related events and organ damage. Lupus nephritis, tobacco smoking, LA-positivity and the use of statins and/or corticosteroids were strongly associated with damage accrual, while hydroxychloroquine seemed to be protective. IgA aPL was not uncommon (16%) in Swedish cases of SLE, and analysis of IgA aPL may add information among clinically suspected APS-patients testing negative for LA and other aPL isotypes.

Despite modern management and tax-funded health care with universal access, almost two thirds of the patients accrued organ damage over time, and the main causes of death were identified as malignancy, infection, and cardiovascular disease. We could confirm well established risk factors for organ damage such as APS, hypertension, and/or the use of corticosteroids, but we also observed that other factors such as pericarditis, haemolytic anaemia, lymphopenia and myositis seems to be of importance in this view (Paper IV).

We also demonstrated that levels of the extracellular matrix protein osteopontin (OPN) was correlated with disease activity in patients with recent-onset SLE. In addition, OPN levels reflected global organ damage and were associated with APS and could have potential as a valuable biomarker in SLE (Paper III).

Additional studies are warranted to further establish the clinical and mechanistic relevance of ANA seroconversion, OPN, as well as the importance of IgA aPL. Vigilance for malignancies, a restricted use of corticosteroids and prevention of cardiovascular disease and APS events are among modifiable factors to prevent organ damage and premature mortality.

This thesis emphasizes the importance of autoantibodies in the pathogenesis, and diagnosis, of SLE. The autoantibody profile can be of great importance for tailored therapy in order to minimize the risk of organ damage accrual, morbidity as well as mortality.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. p. 80
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1731
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-164957 (URN)10.3384/diss.diva-164957 (DOI)9789179298951 (ISBN)
Public defence
2020-04-29, Belladonna, Växthuset, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Rheumatism AssociationRegion ÖstergötlandSwedish Society of MedicineSwedish Society for Medical Research (SSMF)Swedish Heart Lung Foundation
Note

Ytterligare forskingsfinansiärer: Ingegerd Johanssons donation, Selanders stiftelse, Ingrid Asps stiftelse, StiftelsenProfessor Nanna Svartz fond, Stiftelsen Konung Gustaf V:s 80-årsfond och Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse.

Available from: 2020-04-07 Created: 2020-04-07 Last updated: 2020-04-07Bibliographically approved

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