Abstract
BackgroundThe role of the complement system in the pathogenesis of systemic sclerosis (SSc) is controversial. This study investigated the role of the lectin pathway of complement as a mediator of ischemia/reperfusion injury in SSc.MethodsThis is a prospective observational cross-sectional study of 211 SSc patients and 29 patients with Raynaud’s phenomenon in undifferentiated connective tissue disease (UCTD) at risk of developing SSc from two outpatient clinics. Serum levels of lectin pathway proteins (FCN-2, FCN-3, MBL, and MASP-2) and eight MBL2 and FCN2 single-nucleotide polymorphisms (SNP) were analyzed by sandwich-type immunoassays and genotyping and examined for their association with disease manifestations.ResultsLectin pathway protein levels and SNPs were similar between SSc and UCTD patients. FCN-2 levels were however higher in SSc patients with present evidence of digital ulcers (mean 1.4 vs. 1.0 μg/mL, p = 0.05), pitting scars (mean 1.3 vs. 1.0 μg/mL, p = 0.01), and puffy fingers (mean 1.2 vs. 1.0 μg/mL, p = 0.04). Similarly, higher FCN-2 levels were observed in SSc patients with Scl-70 autoantibodies (mean 1.5 vs. 1.0 μg/mL, p = 0.001), interstitial lung disease (mean 1.2 vs. 0.9 μg/mL, p = 0.02), and a forced vital capacity (FVC) below 80% (mean 1.4 vs. 1.0 μg/mL, p = 0.02). In line, variant alleles in the FCN-2 SNP at position + 6359 were associated with a significantly reduced FVC and diffusion capacity. Furthermore, patients with SSc renal crisis harbored higher MBL levels (mean 2.7 vs. 1.5 μg/mL, p = 0.04). No other lectin pathway protein levels or polymorphisms were associated with disease manifestations, low complement C3 and/or C4 levels, or inflammatory markers.ConclusionsThis study does not support a relevant role for several lectin pathway complement proteins in the pathogenesis of SSc. Higher FCN-2 levels were however associated with Scl-70 autoantibody positivity, interstitial lung involvement, and digital vasculopathy. Elevated MBL levels were associated with renal crisis.
Highlights
The role of the complement system in the pathogenesis of systemic sclerosis (SSc) is controversial
Participants We conducted a cross-sectional prospective study of Raynaud’s phenomenon in undifferentiated connective tissue disease (UCTD) at risk of developing SSc [23, 24] and SSc patients enrolled at the University Hospitals of Basel and Zurich as part of the European Scleroderma Trials and Research group centers (EUSTAR) [25]
Demographic and clinical characteristics The study population consisted of 211 patients with established SSc and 29 UCTD patients with visits between 2005 and 2016
Summary
The role of the complement system in the pathogenesis of systemic sclerosis (SSc) is controversial. This study investigated the role of the lectin pathway of complement as a mediator of ischemia/reperfusion injury in SSc. Systemic sclerosis (SSc) is a difficult-to-treat orphan disease that is associated with a considerable morbidity and mortality [1]. Endothelial cell damage and microvascular dysfunction are early and important events in the pathogenesis of SSc and drive the activation of the immune system [4, 5]. The complement system, a complex cascade of circulating and surface-bound proteins that play an essential role in the innate immune defense, has been implicated in certain rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus [6, 7], but its role in SSc is still debated. In several subsequent studies, hypocomplementemia was not associated with SSc disease activity [10,11,12]
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