SIGLEC1 is a biomarker of disease activity and indicates extraglandular manifestation in primary Sjögren's syndrome

Thomas Rose, Franziska Szelinski, Anna Lisney, Karin Reiter, Sarah J Fleischer, Gerd R Burmester, Andreas Radbruch, Falk Hiepe, Andreas Grützkau, Robert Biesen, Thomas Dörner, Thomas Rose, Franziska Szelinski, Anna Lisney, Karin Reiter, Sarah J Fleischer, Gerd R Burmester, Andreas Radbruch, Falk Hiepe, Andreas Grützkau, Robert Biesen, Thomas Dörner

Abstract

Objectives: To evaluate the interferon (IFN) biomarkers sialic acid binding Ig like lectin 1 (SIGLEC1, CD169) and IFN-γ-inducible protein-10 (IP-10) in patients with primary Sjögren's syndrome (pSS).

Methods: 31 patients fulfilling the American-European criteria for pSS were included. Disease activity was obtained by EULAR Sjögren's syndrome disease activity index (ESSDAI). SIGLEC1 expression on monocytes was analysed using flow cytometry. IP-10 concentrations were determined using Bioplex human Cytokine 27-plex kit. Spearman rank test (SRT) was used for correlation analysis and Mann-Whitney U (MWU) to test for differences between glandular and extraglandular manifestations.

Results: An activated IFN system was detected by an upregulation of SIGLEC1 expression in 64.5% and by elevated serum level of IP-10 in 78.9% of our patients with pSS. In a subsequent analysis SIGLEC1 expression was found to be upregulated more frequently in patients with extraglandular manifestations (16/16, 100%) compared to patients with exclusively glandular involvement (4/15, 27%). SIGLEC1 expression could significantly discriminate between these two disease subgroups (p=0.0001, MWU) with a positive predictive value (PPV) of 80% for extraglandular disease. Moreover, the expression correlated with disease activity (p=0.005, r=0.54, SRT). Serum IP-10 levels neither differed significantly between glandular and extraglandular disease nor correlated with ESSDAI.

Conclusions: Our results indicate that increased SIGLEC1 expression characterises patients with systemic involvement and high disease activity. Therefore, SIGLEC1 determination might be of value for subset definition, risk stratification and differential therapeutic considerations in pSS.

Keywords: Cytokines; Disease Activity; Inflammation; Sjøgren's Syndrome.

Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1
Representative FACS plor of SIGLEC1 (CD169) expression on monocytes (CD14+) obtained from HD, pSS and SLE. The SIGLEC1 expression of patient with severe pSS disease acitivity is increased (ID19; ESSDAI 12; CD14/SIGLEC1+ 27.5%; median MFI 771), whereas the SIGLEC1 expression of patients with no pSS disease acitivity (ID6; ESSDAI 0; CD14/SIGLEC1+ 0.58%; median MFI 143) is comparable to HD (CD14/SIGLEC-1+ 1.02%; median MFI 144). Almost all monocytes of a patient with a SLE flare express SIGLEC1. ESSDAI, EULAR Sjögren's syndrome disease activity index; HD, healthy donor; MFI, median fluorescence intensity; pSS, primary Sjögren's syndrome; SIGLEC1, sialic acid binding Ig like lectin 1; SLE, systemic lupus erythematosus.
Figure 2
Figure 2
2/A Comparison of IP-10 and SIGLEC1 levels in healthy donors (HD), patients with glandular (gl.) and extraglandular (egl.) pSS and SLE 2/A. (MWU statistics was used to test for differences). 2/B. Subsequent analysis of pSS subgroups without medication (using MWU test). 2/C.Correlation analysis (using SRT) between disease activity (ESSDAI) of patients with pSS, SIGLEC1 expression (MFI) on monocytes and IP-10 in sera were performed. Red dots refer to patients with documented egl. manifestation, while black dots refer to patients suffering from gl. manifestation only. Dashed lines show calculated thresholds of SIGLEC1 and IP-10. 2/D. Comparison of SIGLEC1 expressions and levels of IP-10 in mild versus moderate to high disease activity. ESSDAI, EULAR Sjögren's syndrome disease activity index; MFI, median fluorescence intensity; MWU, Mann Whitney U Test; no med., no medication; ns, not significant; p values *, p

Figure 3

Mean fluorescence intensity (MFI) of…

Figure 3

Mean fluorescence intensity (MFI) of SIGLEC1 expression before and after introduction of prednisolone…

Figure 3
Mean fluorescence intensity (MFI) of SIGLEC1 expression before and after introduction of prednisolone or hydroxychloroquine. In a separate cohort, the MFI of SIGLEC1 on CD14+ monocytes of patients with either SLE (shown in black) or pSS (shown in red) was measured before and after the introduction of prednisolone or hydroxychloroquine. The average dose was 13.33 mg for prednisolone and 300 mg for hydroxychloroquine; the time period between measurements was ∼5.5 months for prednisolone and 5 months for hydroxychloroquine. Both treatments significantly reduced SIGLEC1 expression (p=0.028 and p=0.046, Wilcoxon test). The dashed line represents the calculated threshold of SIGLEC1 (260.5). pSS, primary Sjögren's syndrome; SIGLEC1, sialic acid binding Ig like lectin 1; SLE, systemic lupus erythematosus.

Figure 4

Distinct IFN pattern in pSS.…

Figure 4

Distinct IFN pattern in pSS. Patients were ordered according their ESSDAI score. Yellow…

Figure 4
Distinct IFN pattern in pSS. Patients were ordered according their ESSDAI score. Yellow colour represents patients with an upregulation of SIGLEC1 and normal IP-10 levels. Blue colour indicates elevated levels of IP-10 but normal expression of SIGLEC1. Red colour indicates and upregulation of SIGLEC1 expression and elevated levels of IP-10. CNS, central nervous system; ESSDAI, EULAR Sjögren's syndrome disease activity index; IFN, interferon; PNS, periperhal nervous system; SIGLEC1, sialic acid binding Ig like lectin 1.
Figure 3
Figure 3
Mean fluorescence intensity (MFI) of SIGLEC1 expression before and after introduction of prednisolone or hydroxychloroquine. In a separate cohort, the MFI of SIGLEC1 on CD14+ monocytes of patients with either SLE (shown in black) or pSS (shown in red) was measured before and after the introduction of prednisolone or hydroxychloroquine. The average dose was 13.33 mg for prednisolone and 300 mg for hydroxychloroquine; the time period between measurements was ∼5.5 months for prednisolone and 5 months for hydroxychloroquine. Both treatments significantly reduced SIGLEC1 expression (p=0.028 and p=0.046, Wilcoxon test). The dashed line represents the calculated threshold of SIGLEC1 (260.5). pSS, primary Sjögren's syndrome; SIGLEC1, sialic acid binding Ig like lectin 1; SLE, systemic lupus erythematosus.
Figure 4
Figure 4
Distinct IFN pattern in pSS. Patients were ordered according their ESSDAI score. Yellow colour represents patients with an upregulation of SIGLEC1 and normal IP-10 levels. Blue colour indicates elevated levels of IP-10 but normal expression of SIGLEC1. Red colour indicates and upregulation of SIGLEC1 expression and elevated levels of IP-10. CNS, central nervous system; ESSDAI, EULAR Sjögren's syndrome disease activity index; IFN, interferon; PNS, periperhal nervous system; SIGLEC1, sialic acid binding Ig like lectin 1.

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