Shin-Ya Kawashiri1, Ayako Nishino2, Takashi Igawa3, Ayuko Takatani3, Toshimasa Shimizu3, Masataka Umeda3, Shoichi Fukui3, Akitomo Okada4, Takahisa Suzuki4, Tomohiro Koga3, Naoki Iwamoto3, Kunihiro Ichinose3, Mami Tamai3, Munetoshi Nakashima5, Akinari Mizokami6, Naoki Matsuoka7, Kiyoshi Migita8, Fumihide Ogawa9, Satoshi Ikeda10, Koji Maemura10, Hideki Nakamura3, Tomoki Origuchi3, Takahiro Maeda11, Atsushi Kawakami3. 1. Departments of Community Medicine and Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. shin-ya@nagasaki-u.ac.jp. 2. Department of Immunology and Rheumatology, and Center for Comprehensive Community Care Education, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 3. Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 4. Department of Internal Medicine, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan. 5. Centre for Rheumatic Diseases, Kurume University Medical Centre, Kurume, Japan. 6. Department of Rheumatology, Isahaya General Hospital, Isahaya, Japan. 7. Nagasaki Medical Hospital of Rheumatology, Nagasaki, Japan. 8. Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan. 9. Ogawa Dermatology and Allergy Clinic, Nagasaki, Japan. 10. Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 11. Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Abstract
OBJECTIVES: To identify prognostic factors among serum biomarkers and endothelial vasodilator function findings in patients with systemic sclerosis (SSc). METHODS: This is a clinical observational study. We assessed 60 consecutive SSc patients (44 limited cutaneous-type, 16 diffuse cutaneous-type). Circulating growth differentiation factor-15 (GDF-15), placenta growth factor (PlGF), endostatin, vascular endothelial growth factor (VEGF), and pentraxin 3 (PTX3) were measured by ELISA. Peripheral endothelial function was measured by forearm blood dilatation response to brachial artery occlusion using noninvasive plethysmography (EndoPAT2000), which is associated with nitric-oxide-dependent vasodilatation and yields a reactive hyperemia index (RHI). We evaluated whether abnormalities in these values were associated with type of SSc - namely, diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) - or organ involvement including interstitial lung disease (ILD), digital ulcer (DU) and estimated right ventricular systolic pressure (RVSP) by echocardiography >30 mmHg. RESULTS: SSc patients showed significantly elevated serum GDF-15, PlGF, endostatin and VEGF but not PTX3 compared with controls. GDF-15 and PlGF were high in dcSSc patients. EndoPAT-RHI was low, and incidence of RVSP >30 mmHg was high in dcSSc. Multivariate analysis revealed that elevated GDF-15 was highly predictive of dcSSc, ILD or RVSP >30 mmHg. PlGF for DU was also found. Conversely, a low EndoPAT-RHI value was predictive of the presence of dcSSc, ILD or DU. CONCLUSIONS: This is the first study to inclusively investigate the relationships among biomarkers, EndoPAT-RHI and organ involvement in patients with SSc. Our data suggest a complex pathological progression of SSc through fibrotic impairment and microvascular damage.
OBJECTIVES: To identify prognostic factors among serum biomarkers and endothelial vasodilator function findings in patients with systemic sclerosis (SSc). METHODS: This is a clinical observational study. We assessed 60 consecutive SSc patients (44 limited cutaneous-type, 16 diffuse cutaneous-type). Circulating growth differentiation factor-15 (GDF-15), placenta growth factor (PlGF), endostatin, vascular endothelial growth factor (VEGF), and pentraxin 3 (PTX3) were measured by ELISA. Peripheral endothelial function was measured by forearm blood dilatation response to brachial artery occlusion using noninvasive plethysmography (EndoPAT2000), which is associated with nitric-oxide-dependent vasodilatation and yields a reactive hyperemia index (RHI). We evaluated whether abnormalities in these values were associated with type of SSc - namely, diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) - or organ involvement including interstitial lung disease (ILD), digital ulcer (DU) and estimated right ventricular systolic pressure (RVSP) by echocardiography >30 mmHg. RESULTS: SSc patients showed significantly elevated serum GDF-15, PlGF, endostatin and VEGF but not PTX3 compared with controls. GDF-15 and PlGF were high in dcSSc patients. EndoPAT-RHI was low, and incidence of RVSP >30 mmHg was high in dcSSc. Multivariate analysis revealed that elevated GDF-15 was highly predictive of dcSSc, ILD or RVSP >30 mmHg. PlGF for DU was also found. Conversely, a low EndoPAT-RHI value was predictive of the presence of dcSSc, ILD or DU. CONCLUSIONS: This is the first study to inclusively investigate the relationships among biomarkers, EndoPAT-RHI and organ involvement in patients with SSc. Our data suggest a complex pathological progression of SSc through fibrotic impairment and microvascular damage.