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Abstract
Background: Pulmonary hypertension (PH) is a life-threatening complication of connective tissue diseases (CTD); in this study, we aimed at investigating the potential role of inducible co-stimulator (ICOS) and its ligand (ICOS-L) as biomarkers of PH in CTD. Materials and Methods: We recruited 109 patients: 84 CTD patients, 13 patients with CTD complicated by pulmonary arterial hypertension (PAH), and 12 subjects with PAH alone. All recruited patients underwent a complete clinical and instrumental assessment along with quantitative measurement of serum ICOS and ICOS-L. Results: Independently of the underlying cause, patients with PAH were older and had a lower glomerular filtration rate. Interestingly, patients with both CTD-related and CTD-unrelated PAH had higher ICOS and ICOS-L serum concentrations than CTD patients (0.0001 for both). When compared to CTD patients, those affected by CTD-PAH showed higher ICOS (440 (240–600) vs. 170 (105–275) pg/mL, p = 0.0001) and ICOS-L serum concentrations (6000 (4300–7000) vs. 2450 (1500–4100) pg/mL; p = 0.0001). In a logistic regression, ICOS and ICOS-L were associated with a diagnosis of PAH, independently from age, gender, and renal function. The corresponding receiver operating characteristic (ROC) curves demonstrated a good diagnostic performance for both ICOS and ICOS-L. Conclusions: ICOS and ICOS-L are increased in patients with PAH, irrespectively from the underlying cause, and represent promising candidate biomarkers for the diagnostic screening for PAH among CTDs patients.
Highlights
Pulmonary hypertension (PH) is a potentially life-threatening complication of connective tissue diseases (CTDs) in general, being frequent in the clinical course of systemic sclerosis (SSc) [1]
Previous reports showed that inducible costimulator (ICOS) serum levels and peripheral T-cell expression were increased in patients with early diffuse cutaneous SSc, and that the overexpression of ICOS leads to increased pro-inflammatory (IFN-γ, IL-17) and pro-fibrotic (IL-4) cytokines synthesis, fibroblast activation, and extracellular matrix synthesis [16,17]
Clinical evaluation, including a comprehensive medical history and a physical examination performed by an experienced clinician; A biochemistry panel including: complete blood count, creatinine and estimated glomerular filtration rate, alanine aminotransferase and aspartate aminotransferase, gamma glutamyl transferase, uric acid, and brain natriuretic peptide (BNP); A 12-lead electrocardiogram with 6-limb and 6 precordial leads with a paper speed set at the standard rate of 25 mm/s; A transthoracic echocardiography (TTE) performed using the Vivid 7 or E9 cardiovascular ultrasound machine by GE Medical Systems (Horten, Norway) with a 1.7/3.4 MHz tissue harmonic transducer
Summary
Pulmonary hypertension (PH) is a potentially life-threatening complication of connective tissue diseases (CTDs) in general, being frequent in the clinical course of systemic sclerosis (SSc) [1]. Life expectancy is significantly better among SSc patients with early rather than late detection of PH [3]. There is a general consensus about the need for regular screening for PH in SSc patients [4]. Previous reports showed that ICOS serum levels and peripheral T-cell expression were increased in patients with early diffuse cutaneous SSc, and that the overexpression of ICOS leads to increased pro-inflammatory (IFN-γ, IL-17) and pro-fibrotic (IL-4) cytokines synthesis, fibroblast activation, and extracellular matrix synthesis [16,17].
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