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Association of Serum C-Reactive Protein Levels With Lupus Disease Activity in the Absence of Measurable Interferon-α and a C-Reactive Protein Gene Variant
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-2125-2931
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.ORCID iD: 0000-0002-0153-9249
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2014 (English)In: Arthritis & rheumatology (Hoboken, N.J.), ISSN 2326-5191, Vol. 66, no 6, 1568-1573 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFN.

Methods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).

Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.

Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene. © 2014 American College of Rheumatology.

Place, publisher, year, edition, pages
Hoboken, NJ, United States: John Wiley & Sons, 2014. Vol. 66, no 6, 1568-1573 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-105501DOI: 10.1002/art.38408ISI: 000337366200018PubMedID: 24574329OAI: oai:DiVA.org:liu-105501DiVA: diva2:707759
Available from: 2014-03-25 Created: 2014-03-25 Last updated: 2015-08-31Bibliographically approved
In thesis
1. Biomarkers and mediators in systemic lupus erythematosus: IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays
Open this publication in new window or tab >>Biomarkers and mediators in systemic lupus erythematosus: IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which may affect multiple organ systems. Interferon alpha (IFNα) and autoantibodies that form immune complexes with nuclear antigens (ANA) are hallmarks believed to drive the disease into a vicious circle of inflammation, tissue damage, autoantigen exposure and autoantibody production.

In SLE, the disease course is characterized by episodes of exacerbations alternating with remissions. In order to best treat the patient it is important to closely monitor symptoms and signs of disease activity. Because of the disease heterogeneity, no single biomarker has yet been found to reflect SLE disease activity in general, although antidouble stranded DNA (anti-dsDNA) antibodies sometimes indicate activity, primarily with renal involvement, and constitutes an item of the SLE disease activity score SLEDAI-2K. However, the method of anti-dsDNA measurement is not standardized and therefore varies between different laboratories. In many other inflammatory conditions, such as rheumatoid arthritis and during bacterial infections, the C-reactive protein (CRP) level is a good indicator of ongoing inflammation, but in SLE and during viral infections, CRP commonly fails to reflect the degree of inflammation. Both viral infections and SLE are characterized by IFNα, and we thus aimed to elucidate whether IFNα can inhibit CRP production. Further, four assays for anti-dsDNA antibody measurements were evaluated with regard to SLE disease specificity and activity, and a new potential biomarker of inflammation, the soluble urokinase plasminogen activator receptor (suPAR), was assessed in relation to disease activity and organ damage.

An in vitro inhibitory effect of IFNα on CRP transcription and production was found in hepatocytes, and this was consolidated by in vivo studies of CRP and IFNα in sera from well-characterized SLE patients (KLURING; Kliniskt lupusregister i nordöstra Götaland). Here, CRP and disease activity were associated among patients without IFNα and without a CRP lowering gene variant (SNP rs1205). The poor disease activity compliance of CRP could therefore be explained, at least in part, by polymorphisms in the CRP gene and increased levels of IFNα. Critical differences between the methods measuring anti-dsDNA were found regarding disease specificity and ability to reflect disease activity and the results suggests the Crithidia luciliae immunofluorescence test (CLIFT) for diagnostic purposes and a bead-based multiplex assay (FIDIS) for monitoring of disease activity. Evaluation of suPAR in SLE revealed no association of suPAR with disease activity, but interestingly instead with accumulated organ damage. suPAR could therefore possibly be used to advert patients at high risk of organ damage.

A detailed biological and clinical characterization of established and emerging SLE biomarkers is of importance since it may improve the clinical management as well as increase the knowledge about disease mechanisms.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1396
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105505 (URN)10.3384/diss.diva-105505 (DOI)978-91-7519-393-9 (ISBN)
Public defence
2014-04-30, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2014-03-25 Created: 2014-03-25 Last updated: 2017-09-08Bibliographically approved

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Enocsson, HelenaSjöwall, ChristopherKastbom, AlfSkogh, ThomasWetterö, Jonas

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