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Systemic sclerosis (SSc) is a connective tissue disease secondary to three cardinal pathological features: immune-system alterations, diffuse microangiopathy, and fibrosis involving the skin and internal organs. The etiology of SSc remains quite obscure; it may encompass multiple host genetic and environmental -infectious/chemical-factors. The present review focused on the potential role of environmental agents in the etiopathogenesis of SSc based on epidemiological, clinical, and laboratory investigations previously published in the world literature. Among infectious agents, some viruses that may persist and reactivate in infected individuals, namely human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and parvovirus B19 (B19V), and retroviruses have been proposed as potential causative agents of SSc. These viruses share a number of biological activities and consequent pathological alterations, such as endothelial dysfunction and/or fibroblast activation. Moreover, the acute worsening of pre-existing interstitial lung involvement observed in SSc patients with symptomatic SARS-CoV-2 infection might suggest a potential role of this virus in the overall disease outcome. A variety of chemical/occupational agents might be regarded as putative etiological factors of SSc. In this setting, the SSc complicating silica dust exposure represents one of the most promising models of study. Considering the complexity of SSc pathogenesis, none of suggested causative factors may explain the appearance of the whole SSc; it is likely that the disease is the result of a multifactorial and multistep pathogenetic process. A variable combination of potential etiological factors may modulate the appearance of different clinical phenotypes detectable in individual scleroderma patients. The in-deep investigations on the SSc etiopathogenesis may provide useful insights in the broad field of human diseases characterized by diffuse microangiopathy or altered fibrogenesis.

Objective This study evaluated Neem oil and Hypericum perforatum (Holoil®) for treatment of scleroderma skin ulcers related to calcinosis (SU-calc). Procedure: We retrospectively analyzed 21 consecutive systemic sclerosis (SSc) patients with a total of 33 SU-calcs treated daily with Holoil® cream compared with a control group of 20 patients with 26 SU-calcs. Holoil® was directly applied to skin lesions, while the control group received only standard medication. Results Application of Holoil® either resulted in crushing and complete resolution of calcium deposits or facilitated sharp excision of calcinosis during wound care sessions in 27/33 cases (81.8%). Complete healing of SU-calc occurred in 15/33 (45%) of cases within a time period of 40.1 ± 16.3 (mean ± SD) days, while 18/33 (55%) of lesions improved in terms of size, erythema, fibrin and calcium deposits. Patients reported a reduction of pain (mean numeric rating scale 7.3 ± 1.9 at baseline versus 2.9 ± 1.4 at follow-up) The control group had longer healing times and a higher percentage of infections. Conclusions The efficacy of local treatment with neem oil and Hypericum perforatum suggest that Holoil® could be a promising tool in the management of SSc SU-calc.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, excessive extracellular matrix deposition, and fibrosis of the skin and internal organs. Several infectious agents, including human herpesvirus-6 (HHV-6), have been suggested as possible triggering factors, but a direct association is still missing. We characterized 26 SSc patients for the presence of HHV-6 in tissues and blood, the anti-HHV-6 response, HLA-G plasma levels, and KIR typing. Given the prominent role of endothelial cells (EC) in SSc pathogenesis, along with HHV-6 tropism for EC, we also investigated the expression of pro-fibrosis factors in HHV-6 infected EC. Results showed the presence of HHV-6A in skin biopsies, and an increased virus load was associated with disease severity and poor natural killer (NK) response against the virus, particularly in subjects exhibiting a KIR2 phenotype. HLA-G plasma levels were significantly higher in HHV-6A/B-KIR2 positive SSc patients and in vitro HHV-6A infection-induced pro-fibrosis factors expression in EC, supporting its role in the development of the fibrosing process. Our data suggest an association between virus infection/reactivation and disease, opening the way to future studies to understand the mechanisms by which HHV-6A might contribute to the multifactorial pathogenesis of SSc.

Objective This study evaluated Neem oil and Hypericum perforatum (Holoil®) for treatment of scleroderma skin ulcers related to calcinosis (SU-calc). Procedure: We retrospectively analyzed 21 consecutive systemic sclerosis (SSc) patients with a total of 33 SU-calcs treated daily with Holoil® cream compared with a control group of 20 patients with 26 SU-calcs. Holoil® was directly applied to skin lesions, while the control group received only standard medication. Results Application of Holoil® either resulted in crushing and complete resolution of calcium deposits or facilitated sharp excision of calcinosis during wound care sessions in 27/33 cases (81.8%). Complete healing of SU-calc occurred in 15/33 (45%) of cases within a time period of 40.1 ± 16.3 (mean ± SD) days, while 18/33 (55%) of lesions improved in terms of size, erythema, fibrin and calcium deposits. Patients reported a reduction of pain (mean numeric rating scale 7.3 ± 1.9 at baseline versus 2.9 ± 1.4 at follow-up) The control group had longer healing times and a higher percentage of infections. Conclusions The efficacy of local treatment with neem oil and Hypericum perforatum suggest that Holoil® could be a promising tool in the management of SSc SU-calc.

Human cytomegalovirus (HCMV) is a highly prevalent opportunistic agent in the world population, which persists as a latent virus after a primary infection. Besides the well-established role of this agent causing severe diseases in immunocompromised individuals, more recently, HCMV has been evoked as a possible factor contributing to the pathogenesis of autoimmune diseases such as systemic sclerosis (SSc). The interplay between HCMV and immune surveillance is supposed to become unbalanced in SSc patients with expanded anti-HCMV immune responses, which are likely involved in the exacerbation of inflammatory processes. In this study, blood samples from a cohort of SSc patients vs. healthy subjects were tested for anti-HCMV immune responses (IgM, IgG antibodies, and T cells to peptide pools spanning the most immunogenic HCMV proteins). Statistically significant increase of HCMV-specific CD8+ T cell responses in SSc patients vs. healthy subjects was observed. Moreover, significantly greater HCMV-specific CD8+ T cell responses were found in SSc patients with a longer disease duration and those with higher modified Rodnan skin scores. Given the known importance of T cells in the development of SSc and that this virus may contribute to chronic inflammatory diseases, these data support a relevant role of HCMV-specific CD8+ T cell responses in SSc pathogenesis.

Background: Systemic sclerosis (SSc) is an autoimmune systemic disease characterized by diffuse fibrosis of skin and visceral organs due to different genetic, infectious, and/or environmental/occupational causative factors, including the inhalation of silica dust. Objectives: To investigate serum trace elements including silicon (s-Si) levels in SSc patients living in a restricted geographical area with high density of worksites with silica exposure hazard. Methods: This case-control study included 80 SSc patients (M:F 10:70; aged 58.4 ± 11.9SD years, mean disease duration 10.1 ± 7.8SD) and 50 age-/sex-matched healthy control subjects consecutively investigated at our University-based Rheumatology Unit. Patients and controls were evaluated for environmental/occupational exposure categories (structured questionnaire), morphological characterization of serum micro-/nanoparticles (Environmental Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy microanalysis), and quantitative assessment of trace elements (inductively coupled plasma atomic emission spectroscopy). Results: Among various categories, only occupational exposure to silica dust was recorded in a significant proportion of SSc patients compared to controls (55% vs. 11%; p