Objective To measure interferon (IFN) inducible chemokines in plasma of patients with systemic sclerosis (SSc) and investigate their correlation with disease severity. Methods We examined the correlation of IFN-inducible chemokines, IFNγ-inducible protein-10 (IP-10/CXCL10), IFN-inducible T cell alpha chemoattractant (I-TAC/CXCL11), and monocyte chemoattractant protein-1 (MCP-1/CCL2) with the IFN gene expression signature. We generated an IFN-inducible chemokine score with the correlated chemokines, IP-10 and I-TAC and compared it in 266 SSc patients enrolled in the GENISOS cohort to that of 97 matched controls. Subsequently, the correlation between the baseline IFN-inducible chemokine score and markers of disease severity was assessed. Finally, the course of IFN-inducible chemokine score over time was examined. Results The plasma IFN-inducible chemokine score correlated with the IFN gene expression signature and this score was higher in SSc patients. It also was associated with the absence of anti–RNA polymerase III antibodies, presence of anti–U1 ribonucleoprotein antibodies (RNP), but not with disease duration, type, or other autoantibodies. The chemokine scores correlated with concomitantly obtained muscle, skin and lung components of the Medsger Severity Index, as well as, FVC, DLco, creatine kinase. Its association with disease severity was independent of anti-RNP or other potential confounders (age, gender, ethnicity, disease duration, and treatment with immunosuppressive agents). Finally, there was not a significant change in the IFN-inducible chemokine score over time. Conclusions The IFN-inducible chemokine score is a stable serological marker of more severe subtype of SSc and may be useful for risk stratification regardless of disease type or duration.

Objective There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort. Methods First, the CRP levels were compared between baseline samples of 266 SSc patients enrolled in the Genetics Versus Environment in Scleroderma Outcome Study cohort and 97 unaffected matched controls. Subsequently, the correlation between CRP levels and concomitantly obtained markers of disease severity was assessed. Serially obtained % predicted forced vital capacity (FVC) was used to examine the long-term ILD progression. The predictive significance of CRP level was investigated by a joint analysis of longitudinal measurements (serial FVCs up to 13 years) and survival data. This approach allowed inclusion of all 1,016 FVC measurements and accounted for survival dependency. Results We confirmed that baseline CRP levels were higher in SSc patients than controls. CRP levels were associated with absence of anticentromere antibodies and correlated with the concomitant severity of lung, skin, and joint involvement. More importantly, higher baseline CRP levels were associated with shorter survival (P < 0.001) and predicted the long-term decline in FVC independent of potential confounders (age at baseline, sex, ethnicity, disease type, current smoking, body mass index, topoisomerase status, and treatment with immunosuppressive agents) in the multivariable model (P = 0.006). Conclusion Baseline CRP levels are predictive of long-term ILD progression. CRP level might aid clinicians in identifying patients that require more intensive monitoring and treatment.

ObjectiveTo evaluate the prognostic significance of baseline electrocardiogram (ECG) abnormalities in a multiethnic cohort of patients with early systemic sclerosis (SSc) and to determine the serological, clinical, and echocardiogram correlates of ECG findings.MethodsSSc patients with disease duration of≤5 years were enrolled in the GENISOS (Genetics versus Environment in Scleroderma Outcome Study) cohort. At the first visit, a standard 12 lead ECG was obtained along with demographic information, clinical data, and autoantibodies. The results of echocardiograms were also recorded. All ECGs were interpreted by a cardiologist unaware of the patients' clinical data.ResultsOf 265 SSc patients with average disease duration at enrollment of 2.5 years, 140 (52.8%) had abnormal ECG findings. These findings were not associated with SSc disease type or autoantibody profile but were associated with more severe heart and lung involvement. A total of 75 patients (28.3%) died over a follow up time of 9.9 years. Complete right bundle branch block (± left anterior hemiblock) on ECG, present in 7 (2.6%) patients, predicted a higher risk of mortality (HR: 5.3; 95% CI: 2.1 to 13.4; p<0.001). The predictive significance of right bundle branch block was independent of age at enrollment, gender, ethnicity and risk factors for coronary artery disease.ConclusionECG abnormalities are common in patients with early SSc and are associated with the severity of lung and heart involvement. Right bundle branch block is an independent predictor of mortality, and should be considered a marker of disease severity in SSc.

Antiphospholipid syndrome is a systemic autoimmune disease associated with thrombosis and recurrent fetal loss in the setting of detectable antiphospholipid (aPL) antibodies. The major antigenic target has been identifed as β2-glycoprotein I (β2GPI), which mediates binding of aPL antibodies to target cells including endothelial cells, monocytes, platelets and trophoblasts, leading to prothrombotic and proinfammatory changes that ultimately result in thrombosis and fetal loss. This article summarizes recent insights into the role of β2GPI in normal hemostasis, interactions between aPL antibodies, β2GPI and cell-surface molecules, molecular prothrombotic and proinfammatory changes induced by aPL antibodies and pathogenic changes leading to fetal loss in antiphospholipid syndrome. New directions in therapy using these insights are examined.

Background The role of cigarette exposure in susceptibility to systemic sclerosis (SSc) has not been previously studied. Our objective was to investigate the association of smoking with susceptibility to SSc in a large well-defined patient population. Methods We conducted a review of 1,379 SSc patients enrolled in the Scleroderma Family Registry and DNA Repository and/or the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort. Smoking history was obtained from chart review or via telephone interview. SSc patients were subsequently categorized as never smokers or ever smokers. SSc patients with available smoking data were matched 2:1 by age, gender, ethnicity and state of residence to controls using the Behavioral Risk Factor Surveillance System. Results The majority of cases were White (74.2%) with Latinos and Blacks representing 11.3% and 9.7%, respectively. Most patients had limited disease type (54%). For our comparative analyses, 621 patients were matched to controls. There was no significant difference in age, gender, ethnicity and SSc disease type between matched versus unmatched patients. The majority of patients had never smoked (57%), while 43% of patients were ever smokers. The SSc patients did not differ in their smoking behavior from controls (p=0.842, OR: 1.020, 95% CI: 0.839–1.240). Anti-topoisomerase positive patients were more likely to be never smokers (p=0.049, OR=0.648, 95% CI=0.421–0.998) whereas no such association was found with the anti-centromere and anti-RNA Polymerase antibodies. Conclusion Unlike in rheumatoid arthritis, smoking does not confer a risk for development of SSc, though it may impact disease severity.