High serum sCD163/sTWEAK ratio is associated with lower risk of digital ulcers but more severe skin disease in patients with systemic sclerosis

Abstract

IntroductionSystemic sclerosis (SSc) is an autoimmune disease characterized by chronic inflammation, vascular injury and excessive fibrosis. CD163 is a scavenger receptor which affects inflammatory response and may contribute to connective tissue remodelling. It has recently been demonstrated that CD163 can bind and neutralize the TNF-like weak inducer of apoptosis (TWEAK), a multifunctional cytokine which regulates inflammation, angiogenesis and tissue remodelling. We aimed to investigate the relationships between serum levels of soluble CD163 (sCD163) and soluble TWEAK (sTWEAK) in relation to disease manifestations in SSc patients.MethodsThis study included 89 patients with SSc who had not received immunosuppressive drugs or steroids for at least 6 months and 48 age- and sex-matched healthy controls (HC) from four European centres. Serum concentrations of sTWEAK and sCD163 were measured using commercially available ELISA kits.ResultsThe mean serum concentrations of sTWEAK were comparable between SSc patients (mean +/- SD: 270 +/- 171 pg/mL) and HC (294 +/- 147pg/mL, P >0.05). Concentration of sCD163 and sCD163/sTWEAK ratio were significantly greater in SSc patients (984 +/- 420 ng/mL and 4837 +/- 3103, respectively) as compared to HC (823 +/- 331 ng/mL and 3115 +/- 1346 respectively, P <0.05 for both). High sCD163 levels and a high sCD163/sTWEAK ratio (defined as > mean +2SD of HC) were both associated with a lower risk of digital ulcers in SSc patients (OR, 95%CI: 0.09; 0.01, 0.71, and 0.17; 0.06, 0.51, respectively). Accordingly, patients without digital ulcers had a significantly higher sCD163 concentration and sCD163/sTWEAK ratio as compared to SSc patients with digital ulcers (P <0.01 for both) and HC (P <0.05 for both). A high sCD163/sTWEAK ratio, but not high sCD163 levels, was associated with greater skin involvement.ConclusionsThe results of our study indicate that CD163-TWEAK interactions might play a role in the pathogenesis of SSc and that CD163 may protect against the development of digital ulcers in SSc. Further studies are required to reveal whether targeting of the CD163-TWEAK pathway might be a potential strategy for treating vascular disease and/or skin fibrosis in SSc.

Serum Soluble CD163 and its association with various disease parameters in patients with systemic sclerosis

“…Our results confirmed the results of others who found an increased serum sCD163 level in patients with SSc compared with that in healthy controls (20)(21)(22).…”

“…This is in agreement with many studies showing that patients with SSc having elevated serum sCD163 levels had significantly higher PASP compared with patients with normal serum sCD163 levels (20,21).…”

“…Furthermore, patients with SSc and increased serum sCD163 levels were more likely to have DU than those with normal serum sCD163 levels, but this difference was not statically significant (p>0.05).This result is inconsistent with other studies that found digital ulcers to be more frequent in patients with SSc having elevated serum sCD163 levels (20,21). This is explained by stating that DUs are related mainly to vascular injury of the digital vessels, characterized by increased intimal thickness and occlusion of the vessel lumen.…”

“…On the other hand, Kowal-Bielecka et al (21) found a lower risk of digital ulceration with elevated serum sCD163 levels and suggested that CD163-positive cells can induce new blood vessel formation through stimulation of endothelial cells proliferation, which may directly contribute to the healing of DU.…”

Role of the tumour necrosis factor‐like weak inducer of apoptosis (TWEAK)/fibroblast growth factor‐inducible 14 (Fn14) axis in autoimmune thyroid disease

“…Here, high levels of sCD163 and a high sCD163/sTWEAK ratio were both correlated with antibody levels in patients with AITD, indicating that increased expression of CD163 plays a vital role in the pathogenesis of AITD and that the CD163/TWEAK axis might be important in the progression of thyroid disease. High CD163/TWEAK ratios have previously been correlated with skin fibrosis in systemic sclerosis (SS) patients, suggesting a possible role for the interplay between CD163 and TWEAK in the pathogenesis of SS . It should be noted that we examined only the soluble forms of these molecules; therefore, it was not possible to determine whether sCD163 is merely a biomarker of inflammatory phenomena or plays an actual role in AITD.…”