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Systemic sclerosis (SSc) is an autoimmune disorder defined ‘vascular’ disease1 due to early defective angiogenesis ending in severe multiorgan fibrosis.2 Biomarker(s) mirroring early microvascular derangements in SSc,3 potentially useful for very early diagnosis, are lacking.
C-X-C angiostatic chemokines induced by interferon-γ, like CXCL10 and CXCL11, are involved in vasculopathy and associate with more severe SSc.4 5 We investigated whether the shift from very early diagnosis of SSc (VEDOSS), when vasculopathy and fibrosis are at very low degree, to definite SSc elicits serum CXCL10/CXCL11 modifications.
CXCL10/CXCL11 were measured by multiplatform bead array in 26 healthy subjects; 62 sera from women admitted to the Scleroderma Clinic of Policlinico Umberto I, Sapienza University of Rome: 34 sera were from VEDOSS6 (mean age 50.50±13.66 years, mean disease duration 11.1±4.2 months) and 28 sera from patients with SSc (mean age 56.56±12.45 years, mean disease 91.3±11.73 months) fulfilling the new American College of Rheumatology/European League Against Rheumatism 2013 classification7; table 1 reports patient characteristics.
Within VEDOSS, 29 subjects had a second blood sample collected during follow-up (T1, 40.67±5.46 months); for each one, we compared baseline (T0) and T1 serum chemokines.Informed consent was obtained.
CXCL10/CXCL11 were significantly higher in SSc (median: CXCL10 497.70 (range: 48.49–2206) pg/mL; CXCL11 107.20 (15.00–882) pg/mL) versus VEDOSS (CXCL10 168.70 (21.66–1202) pg/mL; CXCL11 23.30 (1.47–217.20) pg/mL) or healthy subjects (CXCL10 145.40 (15.86–310.30) pg/mL; CXCL11 10.90 (4.30–189.20) pg/mL) (figure 1A, B). All patients showed serum chemokines stratification according to capillaroscopic patterns (figure 1C, D), while chemokine levels did not significantly differ when related to anti-centromere antibodies or anti-topoisomerase positivity (not shown). VEDOSS subsequently shifted to SSc showed higher baseline chemokines (T0: CXCL10 217 (53.68–469.00) pg/mL; CXCL11 40.57 (15.74–92.04) pg/mL) versus subjects persistent in VEDOSS condition (T0: CXCL10 137.70 (21.66–339) pg/mL; CXCL11 17.47 (1.47–32.03) pg/mL) (figure 1E, F). Only VEDOSS shifted to SSc showed CXCL10/CXCL11 increase at T1 (570.80 (53.25–875.20) pg/mL). Both chemokines were able to discriminate VEDOSS subjects developing SSc (figure 1G, H) with the following cut-off values, identified by receiver operating characteristic (ROC) analysis: CXCL10 ≥165 pg/mL, area under the curve (AUC)=0.70 (95% CI 0.52 to 0.94, p<0.01) with 0.75 sensitivity and 0.70 specificity; CXCL11 ≥29.67 pg/mL, AUC=0.80 (95% CI 0.67 to 0.99, p<0.01) with 0.75 sensitivity and 0.88 specificity. Serum CXCL10 and CXCL11 positively correlated (ρ=0.6, p<0.0001) (figure 1I).
Due to CXCL10/CXCL11 detrimental effects on vessel homeostasis,5 8 9 their higher baseline concentration in VEDOSS thereafter developing SSc likely mirrors the earliest vascular bed alteration(s)/modification(s)/rearrangement(s) occurring when vasculopathy is still at low degree. With vascular damage progression, serum chemokines increased, as suggested by level stratification according to the capillaroscopic patterns. VEDOSS subjects retaining lower CXCL10/CXCL11 overtime (at T0 and T1) did not evolve to definite SSc and maintained normal capillaroscopic pattern.
The small sample size investigated did not allow more robust combined analysis, completed by several validation stages, required by studies on functional biomarkers.10 Result confirmation needs larger sample size, including more clinical variables and closer follow-up. This preliminary cross-sectional/retrospective analysis encourages further and larger works to ascertain if chemokines may be really the turning point from VEDOSS to definite SSc.
The authors thank Dr Silvia Giannattasio, University of Rome “Foro Italico”, for her support and assistance.
SB and CA share the last co-authorship.
SB and CA contributed equally.
Handling editor Josef S Smolen
Contributors All authors were involved in the article drafting and crtitical revisions of important intellectual and experimental contents.All authors approved the final version to be published.
Funding This research was supported by the grant Scientific Independence of young Researchers (SIR) (protocol no. RBSI14D5NX).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Sapienza University of Rome Ethic Committee (protocol no. 2567/15).
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators Dr Silvia Giannattasio.
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