Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy. CXCL4 represents an early serum biomarker of severe SSc and likely contributes to inflammation via chemokine signaling pathways, but the exact role of CXCL4 in SSc pathogenesis is unclear. Here, we elucidate an unanticipated mechanism for CXCL4-mediated immune amplification in SSc, in which CXCL4 organizes “self” and microbial DNA into liquid crystalline immune complexes that amplify TLR9-mediated plasmacytoid dendritic cell (pDC)-hyperactivation and interferon-α production. Surprisingly, this activity does not require CXCR3, the CXCL4 receptor. Importantly, we find that CXCL4-DNA complexes are present in vivo and correlate with type I interferon (IFN-I) in SSc blood, and that CXCL4-positive skin pDCs coexpress IFN-I-related genes. Thus, we establish a direct link between CXCL4 overexpression and the IFN-I-gene signature in SSc and outline a paradigm in which chemokines can drastically modulate innate immune receptors without being direct agonists.

Our results underline the relevance of early microvascular assessment in patients at risk of developing a severe complication such as PAH that can amplify the systemic microvascular impairment in SSc. More severe NVC abnormalities should lead to strict cardiopulmonary surveillance and a complete NVC study is indicated.

Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.

BackgroundNailfoldCapillaroscopy (NC) is a diagnostic and sensitive tool in order to investigate Raynaud's phenomenon (RF) that is the hallmark of both Systemic Sclerosis (SSc) and Very Early Diagnosis Of ScS (VEDOSS) patients. Thus NC is largely used in patients with these conditions and NC specific abnormalities have become a minor criteria in ACR/EULAR SSc Criteria in 2013.ObjectivesAim of our study was to monitor NC changes in a group of 66 VEDOSS patients, enrolled in two EUSTAR center.MethodsWe selected those patients who developed SSc at the follow-up. Moreover, we compared the NC features of these patients with NC of those VEDOSS patients who did not move to SSc, in order to find out NC features, if any, suitable as predictive risk factor for SSc at the time of VEDOSS diagnosis.ResultsIn our 66 VEDOSS patients, 21 of them (19 females, mean age 55 yrs) shifted to SSc in a mean follow-up time of 31 months (range 6–60 months). Table 1 shows the main features of matched VEDOSS patients: Group A with unchanging diagnosis and Group B progressing into SSc. Table 2 shows the progression of NC abnormalities from VEDOSS to established SSc diagnosis in Group B patients.Table 1FeaturesGroup A (n=21)Group B (n=21)Age, yrs (range)50 (28–70)55 (27–77)Sex (M/F)1/202/19Disease duration, month (range)51 (14–70)50 (21–70)Follow up, months (range)–31 (6–60)Anti-centromere Ab (n)1114Anti-Scl70 Ab (n)35ANA positivity (n)72NC PatternNormal = 11 (52.3%)Normal = 8 (38.1%)Early = 7 (33.3%)Early = 8 (38.1%)Active = 2 (9.6%)Active = 4 (19%)Late = 1 (4.8%)Late = 1 (4.8%)Table 2NC ParameterNC at baselineNC at follow-up(VEDOSS diagnosis)(SSc diagnosis)Loop diameter86 μm98 μmApex width176 μm187 μmCapillary distributionSlighty irregular = 11 (52.4%)Slightly irregular = 14 (66.6%)Disorganized = 4 (19%)Disorganized = 6 (28.6%)Capillary density (n/mm2)Normal = 12 ( 57.1%)Normal = 9 ( 42.8%)Reduced = 9 (42.8%)Reduced = 12 (57.1%)Capillary enlargementEnlarged loops = 10 (47.6%)Enlarged loops = 6 (28.6%) (enlarged = 20–50 μm; giant >50 μmGiant loops = 10 (47.6%)Giant loops = 11 (52.4%)Avascular areas (n pts/%)2/9.5%6/28.6%NC Pattern (n)Early = 8 (38%)Early = 5 (23.8%)Active = 4 (19%)Active = 7 (33.3%)Late = 1 (4.7%)Late = 2 (9.5%)Score >1 (n pts)1315When we compared basal NC of Group A and Group B patients, in former VEDOSS developing SScwe found a significantly higher NC score (>1), 13 versus 5 cases (p<0.03) and a larger mean apex width, 177 μm (range 50–640) versus 104 μm (range 10–280) (p<0.005).ConclusionsOur study describes a progression of NC changes during the evolution of early SSc. Moreover we identified some NC features, such as higher NC score and larger apex width, whose presence at the very early diagnosis of SSc may suggests its development in an established disease, thus underlying the relevance of specific NC abnormalities as possible predictive risk factors.Disclosure of InterestNone declared

Introduction Like other autoimmune diseases, systemic sclerosis (SSc) has been described to be associated with accelerated atherosclerosis (ATS). Before clinical manifestations of cardiovascular disease (CVD) occur, subclinical ATS can be investigated in different ways. Aim To evaluate the presence of subclinical ATS in a group of patients with SSc, and to identify different risk profiles among patients. Methods Subclinical ATS was reviewed in 43 SSc patients and 27 healthy controls, using 2 methods: carotid ultrasound and flow mediated dilation (FMD) of the brachial artery. Results Plaques were statistically more frequent in SSc patients than in controls (65% vs 30%, P = .006); intima‐media thickness of common carotid artery (CCA‐IMT) resulted in statistically higher (median value 0.8 mm vs 0.55 mm; P < .0001) while FMD was significantly lower (median value 9% vs 14%; P = .0086) in patients compared to healthy controls. Among the SSc patients, thickening of CCA‐IMT was significantly associated with the presence of diastolic dysfunction of left ventricle (absence of diastolic dysfunction: odds ratio [OR] 0.2, 95% CI 0.04‐0.92, P = .038) and with a higher Framingham score (OR 1.3, 95% CI 1.03‐1.6], P = .024). The diffuse cutaneous form was slightly protective against pathological FMD (OR 0.12, 95% CI 0.022‐0.71, P = .019). Conclusions This study confirms the involvement of macrocirculation in SSc patients, detecting the presence of subclinical ATS markers more frequently in patients compared to healthy controls. Framingham score, diastolic dysfunction of left ventricle and limited cutaneous form of the disease appeared to be associated with a higher risk of developing ATS.