Sjögren's syndrome: epidemiological risk factors and biomarkers
Författare
Summary, in English
Primary Sjögren’s syndrome (pSS) is an autoimmune disease, primarliy affecting women, characterised by inflammation and destruction of exocrine glands with a prevalence of 0.01-0.09%. About one-third of the patients also suffer from extraglandular manifestations e.g. inflammation in the lungs, kidneys, skin or nerves. Apart from dyness symptoms, patients often suffer from fatigue and pain. Little is known about epidemiological risk factors other than a negative association between smoking and pSS.
The aims of this work was to identify epidemiological risk factors for the development of pSS and to analyse biomarkers (cytokines) in relation to found epidemiological risk factors. In Study I, the Malmö Sjögren’s syndrome registry (MSSR) was linked to two large population based prospective health surveys: the Malmö Preventive Medicine Programme (MPMP) and the Malmö Diet and Cancer Study (MDCS). The prediagnostic data aquired from the health studies revealed a negative association between current smoking and a subsequent development of pSS. On the other hand, being a former smoker at the time of the health surveys was associated with a higher risk of later developing pSS.
pSS patients are frequently rheumatoid factor (RF) positive. RF can cross-bind the antibodies used in sandwich Enzyme-Linked Immunosorbent Assays (ELISAs), which is common method for analysing cytokine levels, and cause erroneous results. Study II included an analysis investigating the potential interaction by RF, and/or heterophilic antibodies, in a bead-ELISA platform using sera from four RF positive patients with rheumatoid arthritis and two RF positive patients with pSS. Erroneous high cytokine values were found in all six patients in almost all cytokine measured and the erroneous values were reduced when using a commercial blocker of heterophilic antibodies/RF.
Two studies were performed to further investigate the relation between smoking and pSS. In Study III, smoking status was investigated in relation to disease activity and cytokine expression [Interleukin (IL)-1, IL-2, IL-3, IL-6, IL-8, IL-10, IL-12 (p70), IL-17, IL-18, IL-33, Interferon (IFN)2a, IFN, Epidermal growth factor (EGF), Regulated upon Activation, Normal T-cell Expressed and presumably Secreted (RANTES), FAS-ligand, B-cell activating factor, Tumor Necrosis (TNF)-, and Transforming growth factor-1 (TGF-1)] in 51 consecutive pSS patients. In Study IV, smoking status and cigarette consumption was investigated in relation disease activity and presence of an type I interferon (IFN) signature in 90 consecutive patients. A type I IFN signature was defined as an increased expression of five type I IFN related genes (IFI44, IFI44L, IFIT1, IFIT3 and MxA), analysed using reverse transcriptase polymerase chain reaction (RT-PCR). No associations between smoking status and cytokine expression, presence of an IFN signature or disease activity [as measured by EULAR Sjögren’s Syndorme Disease Activity Index (ESSDAI)] were found. However, high cigarette consumtion (pack-years 8.8 years) was associated to a higher burden of symptoms [as measured by EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI)]
In conclusion we found a negative associaton between current cigarette smoking and subsequent pSS diagnosis but we did not find any associations between cigarette smoking and disease activity, cytokine expression or presens of a type I IFN signature in pSS patients. In both Study III and Study IV current smokers were few, making it difficult to draw any firm conclusions regarding this group.
The aims of this work was to identify epidemiological risk factors for the development of pSS and to analyse biomarkers (cytokines) in relation to found epidemiological risk factors. In Study I, the Malmö Sjögren’s syndrome registry (MSSR) was linked to two large population based prospective health surveys: the Malmö Preventive Medicine Programme (MPMP) and the Malmö Diet and Cancer Study (MDCS). The prediagnostic data aquired from the health studies revealed a negative association between current smoking and a subsequent development of pSS. On the other hand, being a former smoker at the time of the health surveys was associated with a higher risk of later developing pSS.
pSS patients are frequently rheumatoid factor (RF) positive. RF can cross-bind the antibodies used in sandwich Enzyme-Linked Immunosorbent Assays (ELISAs), which is common method for analysing cytokine levels, and cause erroneous results. Study II included an analysis investigating the potential interaction by RF, and/or heterophilic antibodies, in a bead-ELISA platform using sera from four RF positive patients with rheumatoid arthritis and two RF positive patients with pSS. Erroneous high cytokine values were found in all six patients in almost all cytokine measured and the erroneous values were reduced when using a commercial blocker of heterophilic antibodies/RF.
Two studies were performed to further investigate the relation between smoking and pSS. In Study III, smoking status was investigated in relation to disease activity and cytokine expression [Interleukin (IL)-1, IL-2, IL-3, IL-6, IL-8, IL-10, IL-12 (p70), IL-17, IL-18, IL-33, Interferon (IFN)2a, IFN, Epidermal growth factor (EGF), Regulated upon Activation, Normal T-cell Expressed and presumably Secreted (RANTES), FAS-ligand, B-cell activating factor, Tumor Necrosis (TNF)-, and Transforming growth factor-1 (TGF-1)] in 51 consecutive pSS patients. In Study IV, smoking status and cigarette consumption was investigated in relation disease activity and presence of an type I interferon (IFN) signature in 90 consecutive patients. A type I IFN signature was defined as an increased expression of five type I IFN related genes (IFI44, IFI44L, IFIT1, IFIT3 and MxA), analysed using reverse transcriptase polymerase chain reaction (RT-PCR). No associations between smoking status and cytokine expression, presence of an IFN signature or disease activity [as measured by EULAR Sjögren’s Syndorme Disease Activity Index (ESSDAI)] were found. However, high cigarette consumtion (pack-years 8.8 years) was associated to a higher burden of symptoms [as measured by EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI)]
In conclusion we found a negative associaton between current cigarette smoking and subsequent pSS diagnosis but we did not find any associations between cigarette smoking and disease activity, cytokine expression or presens of a type I IFN signature in pSS patients. In both Study III and Study IV current smokers were few, making it difficult to draw any firm conclusions regarding this group.
Avdelning/ar
Publiceringsår
2019
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University, Faculty of Medicine Doctoral Dissertation Series
Volym
2019
Issue
74
Fulltext
Dokumenttyp
Doktorsavhandling
Förlag
Lund University: Faculty of Medicine
Ämne
- Rheumatology and Autoimmunity
Nyckelord
- Sjögren syndrome
- cytokine
- Interferon Type I
- Cigarette smoking
Status
Published
Forskningsgrupp
- Internal Medicine - Epidemiology
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-7619-803-2
Försvarsdatum
20 september 2019
Försvarstid
13:00
Försvarsplats
Lilla aulan, Jan Waldenströms gata 5, Skånes Universitetssjukhus i Malmö
Opponent
- Marja Pertovaara (associate professor)