| Objective:The aim of the study were to define peripheral blood protein biomarkers that distinguish patients of systemic sclerosis(SSc)with and without different stages of interstitial lung disease(ILD)and find clinic risk factors of SSc-ILDMethods:45 patients who met the preliminary SSc criteria of the American Rheumatic Association and European League Against Rheumatism(EULAR)were enrolled in the Department of Rheumatology and Immunology,First Affiliated Hospital of Xiamen University from September 2012 to June 2017.Meanwhile,69 patients with primary Sjogren’s syndrome(pSS)and 44 patients with rheumatoid arthritis(RA)at the same time point were selected as synchronous detection.All patients were older than 18 years old.Serum samples were collected and examined by high resolution CT(HRCT)and pulmonary function tests(PFTs)including forced vital capacity(FVC),forced expiratory volume in one second(FEV1),FEV1/FVC,diffusing capacity for carbon monoxide of lung(DLCO).According to the range,characteristics and degree of ILD lesions in HRCT of each patient,the patients were divided into ILD 0,1,2 and 3 grades.At the same time,clinical information of patients was recorded:disease course,smoking history,drug use,clinical dyspnea score.Multiple Enzyme-linked Immunosorbent Assay(Elisas),chemiluminescent enzyme immunoassay(CLEIA)and Luminex-Xmap were used to detect 42 cytokines/chemokines,matrix metalloproteinases(MMPs)and Krebs von den Lungen-6(KL-6)in serum samples of all patients.Linear regression method is used to analyze data to compare differences of these cytokine levels in different diseases and degrees of ILD.In multiple comparisons,the false discovery rate(FDR)is used to adjust the p value to obtain the error rate,which is defined as a significant correlation when the FDR is less than 0.10.Results:Increased serum levels of KL-6,C-X-C motif chemokine 10/interferon gamma-induced protein10(CXCL10/IP-10)and Eotaxin/CCL11 were significantly associated with ILD disease severities in SSc,pSS and RA(FDR<0.1).In pSS-ILD and RA-ILD,increased levels of KL-6 were significantly correlated with decreased FVC(FDR<0.1).The higher CXCL10/IP-10 was increased,the lower FVC was decreased in SSc-ILD,pSS-ILD and RA-ILD(FDR<0.1).Transforming growth factor-a(TGF-a)was significantly related to ILD severity in RA(FDR<0.1).Increased levels of vascular endothelial growth factor(VEGF)and tumor necrosis factor-a(TNF-a)were significantly correlated with ILD severities in pSS(FDR<0.1).The receiver operating characteristic(ROC)was used to further compare the relative sensitivity and specificity of KL-6,CXCL10/IP-10,EOtaxin/CCL11 in three diseases.The AUCs of KL-6 in SSc-ILD were 0.82(sensitivity 88.89%,specificity 78.95%),the AUCs of KL-6 in pSS-ILD were 0.81(sensitivity 77.14%,specificity 91.43%),and the AUCs of KL-6 in RA-ILD were 0.90(sensitivity 81.82%,specificity 90.91%);The[AUC]values of Eotaxin/CCL11 in SSc-ILD were 0.68(sensitivity 70.37%,specificity 63.16%),the[AUC]values of Eotaxin/CCL11 in pSS-ILD were 0.69(sensitivity 80.00%,specificity 54.29%),and the[AUC]values of Eotaxin/CCL11 in RA-ILD were 0.65(sensitivity 59.09%,specificity 72.73%);The AUCs of CXCL10/IP-10 in SSc-ILD were 0.62(sensitivity 36.84%,specificity 92.59%),and the AUCs of CXCL10/IP-10 in were 0.61(sensitivity 59.09%,specificity 68.18%).KL-6 had the highest sensitivity and specificity in ILD of three diseases compared with CXCL10/IP-10 and Eotaxin/CCL11.For CXCL10/IP-10,the sensitivity and specificity of SSc-ILD were higher than that of RA-ILD.Conclusion:In SSc,the elevated levels of serum KL-6,CXCL10/IP-10 and Eotaxin/CCL11 were consistent with the severities of ILD.The higher levels of the three cytokines were increased,the more serious the severities of ILD got.Similar results were found in pSS and RA.It was also found that increased levels of CXCL10/IP-10 were consistent with decreasing levels of forced vital capacity(FVC)in SSc-ILD.Increased levels of KL-6 had no statistic significant correlation with decreasing levels of FVC.However,in pSS-ILD and RA-ILD,the increased levels of KL-6 was consistent with the decrease of FVC.In addition,the elevated level of TGF-a was significantly correlated with the severities of RA-ILD,and the elevated levels of VEGF and TNF-a were significantly correlated with the severities of pSS-ILD.Therefore,KL-6,CXCL10/IP-10 and Eotaxin/CCL11 can be used not only as effective serum biomarkers for early diagnosis of interstitial lung disease in systemic sclerosis,but also as effective serum biomarkers for interstitial lung disease in primary Sjogren’s syndrome and rheumatoid arthritis. |
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