Increased Levels of ICOS and ICOSL Are Associated to Pulmonary Arterial Hypertension in Patients Affected by Connective Tissue Diseases.

Mattia Bellan,Francesco Murano,Ailia Giubertoni,Veronica Maglione,Roberta Pedrazzoli,Cristina Piccinino,Roberto Piffero,Federico Ceruti,Antonio Acquaviva,Rosalba Minisini,Daniele Sola,Mario Pirisi,Giulia Francesca Manfredi,Giuseppe Patti,Pier Paolo Sainaghi,Stelvio Tonello

doi:10.3390/diagnostics12030704

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

Introduction

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].

Materials and Methods

Results

Discussion