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1.  Skin Gene Expression Correlates of Severity of Interstitial Lung Disease in Systemic Sclerosis 
Arthritis and rheumatism  2013;65(11):2917-2927.
Objective
We undertook this hypothesis-generating study to identify skin transcripts correlating with severity of interstitial lung disease (ILD) in systemic sclerosis (SSc).
Methods
Skin biopsy samples from 59 patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort or an open-label imatinib study (baseline visit) were examined by global gene expression analysis using Illumina HT-12 arrays. Skin transcripts correlating with concomitantly obtained forced vital capacity (FVC) values and the modified Rodnan skin thickness score (MRSS) were identified by quantitative trait analysis. Also, immunofluorescence staining for selected transcripts was performed in affected skin and lung tissue. Plasma levels of CCL2, soluble SELP, and soluble P-selectin glycoprotein ligand 1 (sPSGL-1) were examined in all patients enrolled in the GENISOS cohort (n = 266).
Results
Eighty-two skin transcripts correlated significantly with FVC. This gene list distinguished patients with more severe ILD (FVC <70% predicted) in unsupervised hierarchical clustering analysis (P < 0.001). These genes included SELP, CCL2, and matrix metalloproteinase 3, which are involved in extravasation and adhesion of inflammatory cells. Among the FVC correlates, 8 genes (CCL2, HAPLN3, GPR4, ADCYAP1, WARS, CDC25B, PLP1, and STXBP6) also correlated with the MRSS. Immunofluorescence staining revealed that SELP and CCL2 were also overexpressed in affected skin and lung tissue from SSc patients compared to those from controls. Plasma levels of CCL2 and sPSGL-1 correlated with concomitantly obtained FVC values (r = −0.22, P = 0.001 and r = 0.17, P = 0.015, respectively). This relationship was independent of potential confounders (age, sex, ethnicity, smoking status, anti–topoisomerase I positivity, treatment with immunosuppressive agents, MRSS, disease type, and disease duration).
Conclusion
A limited number of skin transcripts including genes involved in extravasation and adhesion of inflammatory cells correlate with severity of ILD.
doi:10.1002/art.38101
PMCID: PMC3898704  PMID: 23897225
2.  Can Serum Surfactant Protein D or CC-Chemokine Ligand 18 Predict Outcome of Interstitial Lung Disease in Patients with Early Systemic Sclerosis? 
The Journal of rheumatology  2013;40(7):1114-1120.
Objective
To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease.
Methods
The pneumoproteins were determined in the baseline plasma samples of 266 patients with early SSc enrolled in the GENISOS observational cohort. They also were measured in 83 followup patient samples. Pulmonary function tests were obtained annually. The primary outcome was decline in forced vital capacity (FVC percentage predicted) over time. The predictive significance for longterm change in FVC was investigated by a joint analysis of longitudinal measurements (sequentially obtained FVC percentage predicted) and survival data.
Results
SP-D and CCL18 levels were both higher in patients with SSc than in matched controls (p < 0.001 and p = 0.015, respectively). Baseline SP-D levels correlated with lower concomitantly obtained FVC (r = −0.27, p < 0.001), but did not predict the short-term decline in FVC at 1 year followup visit or its longterm decline rate. CCL18 showed a significant correlation with steeper short-term decline in FVC (p = 0.049), but was not a predictor of its longterm decline rate. Similarly, a composite score of SP-D and CCL18 was a significant predictor of short-term decline in FVC but did not predict its longterm decline rate. Further, the longitudinal change in these 2 pneumoproteins did not correlate with the concomitant percentage change in FVC.
Conclusion
SP-D correlated with concomitantly obtained FVC, while CCL18 was a predictor of short-term decline in FVC. However, neither SP-D nor CCL18 was a longterm predictor of FVC course in patients with early SSc.
doi:10.3899/jrheum.120997
PMCID: PMC3728890  PMID: 23588945
SYSTEMIC SCLEROSIS; SURFACTANT D
3.  Anti-Fibrillarin Antibody in African American Patients with Systemic Sclerosis: Immunogenetics, Clinical Features, and Survival Analysis 
The Journal of rheumatology  2011;38(8):1622-1630.
Background
Anti-U3-RNP or anti-fibrillarin antibodies (AFA) are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. The current study examines the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
Methods
Overall, 278 AA SSc patients and 328 unaffected AA controls were enrolled from three North American cohorts. Clinical features, autoantibody profile, and HLA-class-II genotyping were captured. To compare the clinical manifestations, relevant clinical features were adjusted for disease duration. The Cox proportional hazards regression was used to determine the effect of AFA on survival.
Results
Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR=11.5, p<0.0001) and AFA negative SSc patients (OR=5.2, p=0.0002). AFA positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger Perivascular and lower Lung Severity Indices (p=0.004, p=0.014, p=0.019, p=0.092, p=0.006, and p=0.016, respectively). After adjustment for age at enrollment, AFA positive patients did not have different survival compared with patients without AFA (p=0.493).
Conclusion
These findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. Moreover, AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis, and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. However, presence of AFA did not change survival.
doi:10.3899/jrheum.110071
PMCID: PMC3149738  PMID: 21572159
Scleroderma; GENISOS; anti-U3-RNP; digital ulcer; HLA DRB1; and Scleroderma Family Registry
4.  Systemic Sclerosis and Lupus 
Arthritis and rheumatism  2010;62(2):589-598.
Objective
To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE).
Methods
We investigated PB cell samples from 74 SSc patients, 21 healthy controls, and 17 SLE patients using Illumina Human Ref-8 BeadChips and quantitative polymerase chain reaction confirmation. None of the study participants were receiving immunosuppressive agents other than low-dose steroids and hydroxychloroquine. In addition to conventional statistical and modular analysis, a composite score for the interferon (IFN)–inducible genes was calculated. Within the group of patients with SSc, the correlation of the IFN score with the serologic and clinical subtypes was investigated, as were single-nucleotide polymorphisms in a selected number of IFN pathway genes.
Results
Many of the most prominently overexpressed genes in SSc and SLE were IFN-inducible genes. Forty-three of 47 overexpressed IFN-inducible genes in SSc (91%) were similarly altered in SLE. The IFN score was highest in the SLE patients, followed by the SSc patients, and then the controls. The difference in IFN score among all 3 groups was statistically significant (P < 0.001 for all 3 comparisons). SSc and SLE PB cell samples showed striking parallels to our previously reported SSc skin transcripts in regard to the IFN-inducible gene expression pattern. In SSc, the presence of antitopoisomerase and anti–U1 RNP antibodies and lymphopenia correlated with the higher IFN scores (P = 0.005, P = 0.001, and P = 0.004, respectively); a missense mutation in IFNAR2 was significantly associated with the IFN score.
Conclusion
SLE and SSc fit within the same spectrum of IFN-mediated diseases. A subset of SSc patients shows a “lupus-like” high IFN-inducible gene expression pattern that correlates with the presence of antitopoisomerase and anti–U1 RNP antibodies.
doi:10.1002/art.27224
PMCID: PMC2879587  PMID: 20112391

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