Background Systemic sclerosis (SSc) is an inflammatory obliterative microvasculopathy disorder of unknown etiology characterized by fibrosis predominantly in the dermis but also in internal organs. The selectin family of adhesion molecules is responsible for the early stages of extravasation through leukocyte adhesion and recruitment involving initial rolling of leukocytes on the endothelium. L-selectin appears to play a critical role in comparison to P- and E-selectin with L-selectin deficient mice essentially equivalent to normal mice treated with antibodies blocking P- and E-selectin. Furthermore, L-selectin may exert its effect at inflammatory sites by mediating leukocyte-leukocyte interactions that facilitate the recruitment of neutrophils and lymphocytes. Uniquely, L-selectin, shed after cellular activation, retains functional activity in its soluble form and is involved in the regulation of leukocyte attachment to an inflamed endothelium . L-selectin ligands are induced on the endothelium of inflammatory sites and the cutaneous sites of chronic inflammation. Levels of (soluble) sL-selectin have been reported as elevated with concomitant decreased expression on CD8+ cells in SSc suggesting that L-selectin is a possible target for therapeutic modulation of skin damage in diffuse cutaneous disease .
Objectives The purpose of this study is to determine in limited SSc or diffuse SSc whether sL-selectin concentration in plasma is a marker of skin involvement using the modified Rodnan skin score (mRSS) as a parameter of the extent of skin disease.
Methods Nineteen cases with limited SSc and 11 cases with diffuse SSc were evaluated and compared to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to establish the diagnosis of SSc. Skin involvement was assessed using the modified Rodnan skin score. Plasma concentrations of sL-selectin were assessed in patients and controls.
Results The distribution of sL-selectin concentration in plasma appears to be normal, by the Shapiro-Wilk test, for controls (p=0.1329), limited SSc (p=0.4153) and diffuse SSc (p=0.3657). A paired t test for the mean difference in sL-selectin concentration for limited SSc cases compared to their matched controls is statistically insignificant (p=0.2424, 95% CI: -62, 229 ng/ml) while the mean difference for diffuse SSc cases compared to their matched controls is statistically significant (p=0.0369, 95% CI: -362, -14 ng/ml). The mean sL-selectin concentrations for limited SSc and diffuse SSc are significantly different by Welch’s two-sample t test (p=0.0005, 95% CI: 7, 20 ng/ml). The distribution of mRSS seems to be normal, by the Shapiro-Wilk test, for limited SSc (p=0.3300) and diffuse SSc (p=0.2318). Assuming normality, we find no association between mRSS and plasma sL-selectin concentration in limited SSc (p=0.9944) but a statistically significant negative correlation in diffuse SSc (R2=73.11%, p=0.0008). The interpretation of the slope for diffuse SSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration in plasma, the modified Rodnan skin score drops 4.22 (95% CI: 2.29, 6.16).
Conclusions Modulation of circulating L-selectin is a promising target for reducing skin damage in diffuse SSc patients.
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Disclosure of Interest J. Dunne Grant/Research support from: Actelion Pharmaceuticals, Scleroderma Association of British Columbia, S. van Eeden Grant/Research support from: The Heart and Stroke Foundation of Canada, GlaxoSmithKline Inc., and the Canadian Institutes for Health Research, K. Keen Grant/Research support from: Scleroderma Association of British Columbia, Speakers Bureau: Merck Canada Inc.
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