Transition of Care for Adolescents : a Hot Topic
January 12, 2018

Systemic sclerosis

Systemic sclerosis (SSc) is a rare and heterogeneous connective tissue disorder of unknown etiology, characterized by widespread vascular injury and dysfunction, immune deregulation and progressive fibrosis of the skin and internal organs.SSc is typically diagnosed late. The establishment of preliminary criteria for very early diagnosis of systemic sclerosis (VEDOSS) intends to counteract this tendency, as earlier identification and treatment of VEDOSS patients may slow disease progression.

A growing body of evidence supports the concept that SSc is primarily a vascular disease, mediated by autoimmunity and evolving into tissue fibrosis. Angiogenesis – the formation of new vessels from the pre-existing ones – is profoundly disturbed in SSc(1), as well as the vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR) signaling pathway.Altered expression of neuropilin 1 (NRP1), a receptor for both class 3 semaphorins and VEGF-A, might play a role on this process and had not been studied in SSc. The aim of this project was to explore the microvasculopathy and deregulated angiogenesis, namely the possible involvement of the axis NRP1/semaphorin 3A (Sema3A), in 55 SSc patients and 25 VEDOSS patients from two hospital centers.

We found significantly decreased NRP1 levels and expression in SSc and VEDOSS patients, compared to controls, which were in relation with injured microcirculation (“active” and “late”nailfold videocapillaroscopy patterns, digital ulcers and impaired angiogenic capacity)(2). We also uncovered NRP1 as a member of the angiogenesis-related gene program regulated by the transcription factor Friend leukemia integration 1 (Fli1) in dermal microvascular endothelial cells.No differences were found for Sema3A serum levels or expression between patients and controls.

In our study, VEDOSS patients already presented circulating biomarkers of defective angiogenesis and VEDOSS sera significantly altered the normal behavior of endothelial cellsin vitro (namely capillarogenesis, migration and proliferation), in a minor extent versus SSc (3). In conclusion, NRP1 deficiency may be an additional factor in the perturbed VEGF A/VEGFR-2 signaling, contributing to peripheral microvasculopathy and defective angiogenesis in SSc, which are evident from the very early stage of the disease.

1. Matucci-Cerinic M, Manetti M, Bruni C, Chora I, Bellando-Randone S, Lepri G, et al. The “myth” of loss of angiogenesis in systemic sclerosis: A pivotal early pathogenetic process or just a late unavoidable event? Vol. 19, Arthritis Research and Therapy. 2017.
2. Romano E, Chora I, Manetti M, Mazzotta C, Rosa I, Bellando-Randone S, et al. Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis. Ann Rheum Dis. 2016;75(8):1541–9.
3. Chora I, Romano E, Manetti M, Mazzotta C, Costa R, Machado V, et al. Evidence for a Derangement of the Microvascular System in Patients with a Very Early Diagnosis of Systemic Sclerosis. J Rheumatol. 2017 Aug;44(8):1190-1197. Epub 2017 May 15.

Adapted from Manetti M, et al. Arthritis Res Ther. 2016;18:36.