Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis

• Published in: Arthritis research & therapy Vol. 20; no. 1; p. 185
• Main Authors: Rice, Lisa M, Mantero, Julio C, Stratton, Eric A, Warburton, Rod, Roberts, Kari, Hill, Nicholas, Simms, Robert W, Domsic, Robyn, Farber, Harrison W, Layfatis, Robert
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16.08.2018; BioMed Central; BMC
• Subjects: Aged; Aged, 80 and over; Arthritis; Biological markers; Biomarkers; Biomarkers - blood; Causes of; Classification; Complications and side effects; Development and progression; Diagnosis; Early Diagnosis; Female; Follistatin-Related Proteins - blood; Gene expression; Health aspects; Humans; Hypertension, Pulmonary - blood; Hypertension, Pulmonary - diagnosis; Hypertension, Pulmonary - etiology; Identification; Male; Medical diagnosis; Medical prognosis; Medical research; Middle Aged; Midkine - blood; Mortality; Pathogenesis; Patients; Physiological aspects; Proteins; Proteomic; Proteomics; Pulmonary arterial hypertension; Pulmonary arteries; Pulmonary hypertension; Scleroderma; Scleroderma (Disease); Scleroderma, Systemic - blood; Scleroderma, Systemic - complications; Sensitivity and Specificity; Skin diseases; Systemic sclerosis; Ultrasonic imaging; United States; Biomarkers; Pulmonary arterial hypertension; Scleroderma; Classification; Proteomic
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-018-1679-8

Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of death in SSc. Identification of a serum-based proteomic diagnostic biomarker for SSc-PAH would allow for rapid non-invasive screening and could positively impact patient survival. Identification and validation of novel proteins could potentially facilitate the identification of SSc-PAH, and might also point to important protein mediators in pathogenesis. Thirteen treatment-naïve SSc-PAH patients had serum collected at time of diagnosis and were used as the discovery cohort for the protein-expression biomarker. Two proteins, Midkine and Follistatin-like 3 (FSTL3) were then validated by enzyme-linked immunosorbent assays. Midkine and FSTL3 were tested in combination to identify SSc-PAH and were validated in two independent cohorts of SSc-PAH (n = 23, n = 11). Eighty-two proteins were found to be differentially regulated in SSc-PAH sera. Two proteins (Midkine and FSTL3) were also shown to be elevated in publicly available data and their expression was evaluated in independent cohorts. In the validation cohorts, the combination of Midkine and FSTL3 had an area under the receiver operating characteristic curve (AUC) of 0.85 and 0.92 with respective corresponding measures of sensitivity of 76% and 91%, and specificity measures of 76% and 80%. These findings indicate that there is a clear delineation between overall protein expression in sera from SSc patients and those with SSc-PAH. The combination of Midkine and FSTL3 can serve as an SSc-PAH biomarker and are potential drug targets for this rare disease population.