Table 1.
Main biomarkers associated with SSc-ILD
| Category | Biomarker | Diagnosis | Prognosis | Therapeutic response prediction | Comments | References |
|---|---|---|---|---|---|---|
| Alveolar epithelial markers | SP-D and SP-A | + | – | + | Serum level (SP-D) associated with anti-topoisomerase I antibody predicts SSc-ILD with 97% ss, 69% sp, a 80% PPV and a 95% NPV (large prospective study) | [11–21] |
| SP-D level <200 ng/ml during treatment predicts good response (small restrospective study) | ||||||
| SP-A: low ss and few studies | ||||||
| KL-6 | – | – | + | High KL-6 serum value (>923 U/ml) associated with more severe pulmonary functional impairment (large prospective trial) | [16, 20–28] | |
| KL-6 serum level remaining >2000 U/ml under treatment predicts poor TR (small retrospective trial) | ||||||
| Chemotactic molecules | CCL18 | – | + | NK | Serum value needs to be associated with patient gender and immunosuppressive drug use for a more precise evaluation of prognosis (large prospective study) | [16, 29–32] |
| CCL2 | + | + | NK | Higher serum levels (>0.66 ng/ml) = worse functional, clinical and mortality outcome (large prospective studies) | [33, 34] | |
| CXCL10 | + | +/– (conflicting evidence) | NK | 2 studies (n = 31 and 74) finding no association between CXCL10 and prognosis | [35–37] | |
| 1 retrospective study (n = 143) finding association between CXCL10 and worse pulmonary functional outcome | ||||||
| Extracellular matrix remodelling. | MMP-7 | + | – | NK | Serum level >1.28 ng/ml ss 89.5%, sp 73.3% for ILD diagnosis in case of systemic sclerosis (small prospective study) | [19, 38] |
| MMP-12 | + | + | NK | High negative correlation with FVC (small prospective study) | [39] | |
| MMP-13 | – | + | NK | Lower serum levels (<50.2 ng/ml) = worse pulmonary functional prognosis (Low level of evidence) | [40] | |
| TIMP-1 and -2 | + | + | NK | Weak but significant correlation between TIMP-1, TIMP-2 and DLCO Low level of evidence | [41, 42] | |
| Endothelial cell adhesion and activation | ECAA | Conflicting evidence | Conflicting evidence | NK | [43, 44] | |
| ET-1 | + | – | NK | Studies of endothelin receptors antagonists for SSC-ILD treatment are inconclusive | [45–47] | |
| Low level of evidence | ||||||
| Selectins (E and P) | + | – | NK | Higher serum levels in SSc | [28, 48, 49] | |
| Low level of evidence | ||||||
| sICAM-1 | + | + | NK | Higher serum levels = worse functional prognosis | [28] | |
| Small prospective study | ||||||
| Fibrogenesis | TGF-β | – | NK | NK | Associated to extrapulmonary disease severity | [50] |
| Small prospective study | ||||||
| CTGF | + | + | NK | High serum levels correlated with lower pulmonary functional tests | [51] | |
| Low level of evidence | ||||||
| GDF-15 | + | + | NK | Higher serum levels (>370 pg/ml) = worse pulmonary functional outcome (prospective studies: n = 115 for the largest) | [52–54] | |
| YKL-40 | + | + | NK | Higher serum levels (>275 µg/ml) associated with worse functional and clinical outcome and mortality (small prospective study) | [37, 55, 56] | |
| Acute-phase reactant | CRP | + | + | + | Serum level >8 mg/l associated with more frequent ILD, worse pulmonary functional involvement and increased mortality (large prospective study) | [20, 57–59] |
| High baseline CRP serum level is associated with poor TR (small retrospective study) | ||||||
| IL-6 | + | + | NK | Serum levels >7.67 pg/ml associated with more frequent and more severe ILD and increased mortality in early disease (large prospective cohort, n = 212) | [36, 60] | |
| Circulating cells | Fibrocytes | + | NK | NK | Increase serum levels associated with more frequent ILD (small studies) | [61–63] |
| In IPF, serum levels >5% associated with increased mortality | ||||||
| Circulating endothelial progenitors | – | + | NK | Higher circulating levels associated with more severe ILD | [64] | |
| Low level of evidence | ||||||
| Anti-topoisomerase T lymphocyte | + | + | NK | Increased serum levels associated with more severe ILD | [65] | |
| Low level of evidence | ||||||
| Th22 lymphocytes | + | – | NK | Increased serum levels associated with more frequent ILD | [66] | |
| Low level of evidence | ||||||
| miRNA | mIR-155 | + | + | NK | Increased serum levels associated with more frequent and more severe ILD | [67] |
| Low level of evidence | ||||||
| miR-142-3p and mIR-92-a | + | – | NK | Lower serum levels associated with ILD | [68, 69] | |
| Low level of evidence | ||||||
| mIR-200-c | + | + | NK | Increased serum levels associated with more frequent and more severe ILD | [70] | |
| Low level of evidence |
Low level of evidence small study(ies): trial with <100 patients with SSc-ILD. Large studies: >100 SSc-ILD patients. CCL18, -2: chemokine ligand 18, 2; CXCL10: chemokine ligand 10; CTGF: connective tissue growth factor; DLCO: lung diffusion capacity for carbon monoxyde; ECAA: endothelial cell autoantibody; ET-1: endothelin-1; FVC: forced vital capacity; GDF-15: growth differentiation factor 15; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; KL-6: Krebs Von Den Lungen 6; miR: microRNA; NPV: negative predictive value; NK: not known; PPV: positive predictive value; sICAM: soluble intercellular adhesion molecule; sp: specificity; SP-A and D: surfactant proteins A and D; ss: sensitivity; SSc-ILD: SSc-associated interstitial lung disease; Th: lymphocytes T helper; TIMP1–2: tissular inhibitor of metalloproteinase 1–2; TR: treatment response; YKL-40: chitinase 3 like protein 1.