RESULTS: Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29% ABSTRACT ObjectivesTo determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfi lling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Results Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fi brosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the nonSSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%).Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modifi ed Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fi brosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.Systemic sclerosis (SSc) is a multisystem disease with vascular, infl ammatory and fi brotic components.

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Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.

IntroductionT helper (Th) cells may differentiate into distinct functional subsets according to the circumstances in which naive precursors encounter the nominal antigen for which they are specific. In the presence of interleukin-12 (IL-12), Th precursor cells become Th1 and high producers of interferon-␥ (IFN-␥), whereas in the presence of IL-4 they become Th2 and high producers of IL-4 and IL-5. These subsets have fundamentally different effector functions, in particular for their capacity to induce monocytes activation. 1 Recently, a distinct Th subset has been characterized in mice 2-6 and humans [7][8][9][10][11] for its high production of IL-17, the use of retinoid-related orphan receptor ␥t (ROR␥t) as master transcription factor, 12 its role in protection against extracellular bacteria and fungi, and in the pathogenesis of several autoimmune conditions, such as collageninduced arthritis, experimental autoimmune encephalomyelitis, and an animal model of inflammatory bowel disease. 4,13,14 Of interest, the generation of Th17 from naive precursors may follow different requirements in mice and humans. In mice, commitment to the Th17 lineage is dependent on transforming growth factor-␤ (TGF-␤), IL-1␤, and IL-6, whereas in humans IL-1␤ and IL-6 but not TGF-␤ appear to be required. 10,[15][16][17][18] The role of IL-23 in Th17 differentiation and effector function is still debated. IL-23 is a member of the IL-6 family of cytokines that shares with IL-12 the p40 subunit and has a unique p19 subunit. 19 IL-23 promotes Th17 responses in vivo but may be more important for the survival and population expansion of Th17 cells than for Th17 lineage commitment. 3,5,16 However, in conjunction with IL-1, IL-23 is sufficient for inducing naive human T cells to produce IL-17A, IL-17F, IL-22, IL-26, IFN-␥, C-C chemokine ligand 20 (CCL20)/ macrophage inflammatory protein 3␣ (MIP-3␣), and the transcription factor ROR␥t. 10 Moreover, mice lacking IL-23 are fully resistant to experimental autoimmune encephalomyelitis, collageninduced arthritis, and inflammatory bowel disease.The pattern of chemokine receptors expressed varies according to the differentiation stage and effector function of T cells. 20 The preferential expression of C-C chemokine receptor 6 (CCR6) distinguishes human Th17 from other Th subsets. 7,8,21,22 It should be stressed, however, that expression of CXC chemokine receptor 3 (CXCR3) within CCR6 ϩ T cells identifies T cells with preferential IFN-␥ production in response to purified protein derivative, whereas IL-17 production in response to Candida albicans hyphae is restricted to CCR6 ϩ CCR4 ϩ cells. 7 IL-17, when overexpressed in murine knee joint, causes inflammation and bone erosion. 23 Likewise, erosion observed in streptococcal cell wall-induced arthritis is highly reduced in IL-17R Ϫ/Ϫ and is associated with impaired expression of matrix metalloproteinases (MMPs). 24 T-cell clones producing IL-17 were generated from the synovium and synovial fluid of rheumatoid arthritis patients, 25 and IL-17 was shown t...

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.