Dilia Giuggioli

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.

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.

Persistent fatigue (defined as ongoing exhaustion, disproportionate to exertion and not adequately alleviated by rest) reduces health-related quality of life of systemic sclerosis (SSc) patients. Fatigue in SSc is associated with reduced capacity to carry out daily activities, work disability and impaired physical function. Clinical studies demonstrated a high prevalence of autoimmune thyroiditis and hypothyroidism in patients with SSc. Since hypothyroidism and the associated fatigue symptoms could be cured by L-thyroxine (L-T4) substitutive therapy, the evolution of fatigue symptoms in SSc hypothyroid patients treated with substitutive therapy has been recently evaluated, showing an amelioration of the fatigue symptoms. We have treated 10 clinical hypothyroid and 23 subclinical hypothyroid female SSc patients (all with diffuse scleroderma) with L-T4 substitutive therapy. Mean baseline General Fatigue Index scores in hypothyroid SSc (15.7±5.1) were significantly higher (greater fatigue; p<0.01) than in the same patients after reaching euthyroidism at 4 months (9.6±3.1). The results suggest that female SSc patients could be screened for thyroid function, overall in presence of fatigue symptoms, and that an appropriate L-T4 substitutive therapy could be useful to mitigate these symptoms. Further studies are needed in larger samples of hypothyroid patients with SSc to confirm these data. Further longitudinal studies could be also aimed to evaluate if L-T4 therapy could be useful in alleviating complications of SSc (such as skin thickness, pulmonary hypertension, etc.).

Aims: To describe a case of systemic sclerosis (SSc) associated with severe alopecia areata (AA) responsive to topical and systemic treatments, including vasoactive and immunosuppressive drugs (mycophenolate mofetil).

Interferon (IFN)-γ-induced protein 10 (IP-10/CXCL10) and its receptor, C-X-C motif receptor 3, appear to contribute to the pathogenesis of hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC) (HCV+MC). The secretion of CXCL10 by cluster of differentiation (CD) CD4+, CD8+, and natural killer-T cells is dependent on IFN-γ, which is itself mediated by the interleukin-12 cytokine family. Under the influence of IFN-γ, CXCL10 is secreted by several cell types including lymphocytes, hepatocytes, endothelial cells, fibroblasts, etc. In tissues, recruited T helper 1 lymphocytes may be responsible for enhanced IFN-γ and tumour necrosis factor-α production, which in turn stimulates CXCL10 secretion from the cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. High levels of CXCL10 in circulation have been found in HCV+MC, especially in patients with clinically active vasculitis. Furthermore, HCV+MC patients with autoimmune thyroiditis (AT) have higher levels than those without AT. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis, and to evaluate whether CXCL10 is a novel therapeutic target in HCV-related MC.

Digital ulcers (DU) may develop in half of systemic sclerosis (SSc) patients; they are often resistant to treatments. Deep wound debridement is crucial for DU healing, but very difficult to carry out without adequate procedural pain management. Here, we report the results of our experience on procedural pain management in scleroderma DU. The study included 51 DU observed in 32 consecutive SSc patients; procedural pain was treated following a definite schedule: local lidocaine and prilocaine (25 mg of either agent per gram of cream, EMLA 5%) were initially used in all cases, followed by local and oral morphine, according to the severity of pain scored on a 10 cm visual analogue scale (VAS). At baseline, higher pain VAS was recorded in more severe (p=0.0001) and/or infected DU (p=0.0001). Good compliance to DU debridement was observed in patients with mild pain (VAS ≤4) treated with only EMLA, and in 5 cases with moderate-severe pain (VAS >4) at baseline. While, the majority of DU with moderate-severe pain (34/39) needed a combined therapy with EMLA and local morphine (8/34) or with EMLA, local and oral morphine (26/34). On the whole, pain management during DU debridement required only EMLA application in 33% of cases, EMLA plus local morphine in 16%, while combined EMLA, local and oral morphine were necessary in 51%, generally with more severe and/or infected lesions. The present study showed valuable control of procedural pain during DU debridement with sequential, combined analgesic treatment.