Systemic Sclerosis 2011

Microvascular damage and dysfunction represent the earliest morphological and functional markers of systemic sclerosis (SSc), a progressive connective tissue disease characterized by vascular abnormalities and diffuse fibrosis in the skin and internal organs. These early microvascular changes are clinically mirrored by Raynaud phenomenon, which can be primary (idiopathic) or secondary to several different conditions including SSc. Morphological and functional assessment of the cutaneous microvasculature have crucial implications for diagnosis, prognosis and therapy in SSc and secondary Raynaud phenomenon. Most importantly, imaging with nailfold videocapillaroscopy (NVC) enables the early differentiation between primary and secondary Raynaud phenomenon by identifying morphological patterns specific to various stages of SSc ('early', 'active' and 'late' patterns); the inclusion of these NVC patterns could increase the sensitivity of classification criteria for SSc. Findings on NVC are also markers of SSc severity and progression, as reduced capillary density has been associated with a high risk of developing digital skin ulcers and pulmonary arterial hypertension. Laser Doppler imaging and thermal imaging demonstrate the dysfunctional cutaneous blood flow in response to cold stimuli. Therapies targeting underlying vascular disease in SSc have been successfully designed to improve the symptoms of Raynaud phenomenon and to reduce ischemic injury to involved organs, and NVC patterns have been found to improve following targeted therapy; however, treatment of later fibrosis remains a challenge.

Systemic sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis affecting the skin, internal organs, and vasculature. Vascular disease with intimal proliferation and obliterative vasculopathy is extremely prevalent in SSc, most commonly manifesting as Raynaud's phenomenon and digital ulcerations. Other manifestations of vascular disease occur less frequently in patients with SSc, including ischemic digital loss, pulmonary arterial hypertension (PAH), and renal crisis. Vascular disease in SSc may also commonly affect pregnancy outcomes and sexual function. Finally, patients with SSc can rarely suffer from inflammatory vasculitis, and recognition of this has a significant impact on therapy. In this special issue on vascular disease in systemic sclerosis, we invited original research articles and review articles regarding the pathogenesis, epidemiology, natural history, evaluation, and/or management of vascular complications in patients with SSc.

Novel therapies in SSc.

FRI0278 Macrovascular Dysfunction of Upper and Lower Limbs Correlates with Digital Ulcerations in Patients with Systemic Sclerosis

Tackling systemic sclerosis from all angles.

Systemic sclerosis is a systemic fibrosing disorder associated with significant morbidity and mortality, with no universally accepted disease-modifying therapy. Significant advances in the understanding of systemic sclerosis in recent years have guided the exploration of biological drugs in systemic sclerosis. In this narrative review, we summarize the published literature on biologic therapies in systemic sclerosis. A double-blind randomized trial, and an open label trial of tocilizumab (which antagonizes the interleukin 6 receptor), identified potential benefits in skin and lung fibrosis in systemic sclerosis; however, these differences failed to attain statistical significance. Two open-label trials compared rituximab (which depletes B lymphocytes) to conventional treatment/ cyclophosphamide in systemic sclerosis-associated interstitial lung disease (ILD), and revealed significant improvements in lung functions and skin disease with rituximab. Significant observational data also support the use of rituximab in skin, lung, muscle and joint manifestations of systemic sclerosis. Abatacept (which blocks T lymphocyte activation) has demonstrated utility for skin and joint disease in systemic sclerosis; a recent clinical trial failed to demonstrate benefits in improving skin thickness compared to placebo. Agents targeting type I interferons, interleukin 17 pathway, CD19 and plasma cells hold promise in systemic sclerosis; however, high-quality evidence is lacking. The results of different ongoing clinical trials targeting B lymphocytes, T lymphocytes, various cytokines (interleukins 6, 17, 4, 13, IL-1α), platelet-derived growth factor receptor, proteasome, integrins or oncostatin M may help guide future therapeutic regimens with biological agents in systemic sclerosis.

To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

AB0628 Macrovascular dysfunction of upper and lower limbs correlates with digital ulcerations in patients with systemic sclerosis

Developing a core set of outcome measure domains to study Raynaud's phenomenon and digital ulcers in systemic sclerosis: Report from OMERACT 2020

POS0424 DETERMINING CIRCULATING ENDOTHELIAL CELLS USING CELLSEARCH SYSTEM IN SYSTEMIC SCLEROSIS PATIENTS

Clinical approach to scleroderma.

Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry.

Effect of mycophenolate mofetil dose on antibody response following initial SARS-CoV-2 vaccination in patients with systemic sclerosis.

Background: Systemic sclerosis (SSc) is characterized by endothelial dysfunction leading to progressive vascular injury and fibrosis. While microvascular involvement is well established as an early disease feature, macrovascular disease has been historically underrecognized and poorly investigated in very early disease stages. Integrated assessments across the SSc spectrum, including very early diagnosis of systemic sclerosis (VEDOSS), remain limited. Methods: In this cross-sectional observational study, patients with established SSc, VEDOSS, and primary Raynaud's phenomenon (PRP) were prospectively enrolled between October 2023 and April 2025. Participants underwent comprehensive microvascular and macrovascular evaluation, including nailfold videocapillaroscopy, multisegmental arterial Doppler ultrasound (carotid, aortic, and lower limb districts), flow-mediated dilation, and measurement of endothelial biomarkers (vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and circulating endothelial cells (CECs)). Traditional cardiovascular risk was estimated using Systematic Coronary Risk Estimation 2 (SCORE2). Results: Sixty-two female subjects were included (34 SSc, 14 VEDOSS, and 14 PRP). Microvascular abnormalities followed the expected disease continuum, with capillaroscopic changes present in 57% of VEDOSS and 91% of SSc patients. Although SCORE2 estimates and carotid intima-media thickness were comparable across groups, macrovascular abnormalities were more frequent in SSc (52.9%) and VEDOSS (50%) compared with PRP (21.4%). VCAM-1, ICAM-1, and CEC levels were significantly increased in SSc compared with PRP, whereas no significant differences were observed between VEDOSS and PRP. Conclusions: These findings support a unified micro- and macro-vascular disease model in SSc and demonstrate that macrovascular involvement is detectable already in the VEDOSS phase. Conventional cardiovascular risk scores underestimate the true vascular burden, highlighting the need for disease-specific risk stratification tools integrating vascular imaging and endothelial biomarkers.

Stress Echocardiographic Prediction of Emerging Pulmonary Vascular Disease in Systemic Sclerosis