Abstract
BackgroundSystemic 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.MethodsThirteen 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).ResultsEighty-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%.ConclusionsThese 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.
Highlights
Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of death in systemic sclerosis (SSc)
We hypothesized that wide-scale proteomic studies of serum might identify a diagnostic biomarker of SSc-PAH. This hypothesis was further supported by our previous small proteomic study, in which we identified 17 cytokines associated with SSc-PAH [17]
Pathway analysis of protein expression SOMAScan protein expression was evaluated in sera from 13 subjects with limited cutaneous systemic sclerosis (lcSSc)-PAH and 16 subjects with lcSSc and no clinical evidence of PAH (Table 1)
Summary
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 noninvasive screening and could positively impact patient survival. Twelve percent of SSc patients will develop SSc-associated pulmonary arterial hypertension (SSc-PAH); these patients have an estimated 50% 3-year survival [1]. Earlier diagnosis and treatment with PAH-specific therapeutics is associated with better outcomes in patients with SSc-PAH [5, 6]. Identification of a diagnostic biomarker that would allow for rapid non-invasive screening could positively impact patient survival, supplement current screening methods, and potentially reduce the need for diagnostic RHC. Transthoracic echocardiography is the most widely accepted screening tool for the diagnosis of SSc-PAH.
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