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1.  Interferon Inducible Chemokines Correlate with Disease Severity in Systemic Sclerosis 
Arthritis and rheumatism  2013;65(1):226-235.
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.
doi:10.1002/art.37742
PMCID: PMC3687352  PMID: 23055137
2.  Irritable bowel syndrome and organic diseases: A comparative analysis of esophageal motility 
AIM: To assess the esophageal motility in patients with irritable bowel syndrome (IBS) and to compare those with patients with autoimmune disorders.
METHODS: 15 patients with IBS, 22 with systemic lupus erythematosus (SLE) and 19 with systemic sclerosis (SSc) were prospectively selected from a total of 115 patients at a single university centre and esophageal motility was analysed using standard manometry (Mui Scientific PIP-4-8SS). All patients underwent esophago-gastro-duodenoscopy before entering the study so that only patients with normal endoscopic findings were included in the current study. All patients underwent a complete physical, blood biochemistry and urinary examination. The grade of dysphagia was determined for each patient in accordance to the intensity and frequency of the presented esophageal symptoms. Furthermore, disease activity scores (SLEDAI and modified Rodnan score) were obtained for patients with autoimmune diseases. Outcome parameter: A correlation coefficient was calculated between amplitudes, velocity and duration of the peristaltic waves throughout esophagus and patients’ dysphagia for all three groups.
RESULTS: There was no statistical difference in the standard blood biochemistry and urinary analysis in all three groups. Patients with IBS showed similar pathologic dysphagia scores compared to patients with SLE and SSc. The mean value of dysphagia score was in IBS group 7.3, in SLE group 6.73 and in SSc group 7.56 with a P-value > 0.05. However, the manometric patterns were different. IBS patients showed during esophageal manometry peristaltic amplitudes at the proximal part of esophagus greater than 60 mmHg in 46% of the patients, which was significant higher in comparison to the SLE (11.8%) and SSc-Group (0%, P = 0.003). Furthermore, IBS patients showed lower mean resting pressure of the distal esophagus sphincter (Lower esophageal sphincter, 22 mmHg) when compared with SLE (28 mmHg, P = 0.037) and SSc (26 mmHg, P = 0.052). 23.5% of patients with SLE showed amplitudes greater as 160 mmHg in the distal esophagus (IBS and SSc: 0%) whereas 29.4% amplitudes greater as 100 mmHg in the middle one (IBS: 16.7%, SSc: 5.9% respectively, P = 0.006). Patients with SSc demonstrated, as expected, in almost half of the cases reduced peristalsis or even aperistalsis in the lower two thirds of the esophagus. SSc patients demonstrated a negative correlation coefficient between dysphagia score, amplitude and velocity of peristaltic activity at middle and lower esophagus [r = -0.6, P < 0.05].
CONCLUSION: IBS patients have comparable dysphagia-scores as patients with autoimmune disorders. The different manometric patterns might allow differentiating esophageal symptoms based on IBS from other organic diseases.
doi:10.3748/wjg.v19.i38.6408
PMCID: PMC3801311  PMID: 24151359
Irritable bowel syndrome; Systemic lupus erythematosus; Systemic sclerosis; Esophageal manometry; Dysphagia
3.  The Role of Type 1 Interferon in Systemic Sclerosis 
Systemic Sclerosis (Scleroderma, SSc) is an autoimmune disease characterized by vasculopathy, inflammation, and fibrosis that can lead to loss of organ function. Type I interferons (IFNs) are family of cytokines that mitigate the deleterious effects of viral and bacterial infections in the innate immunity system. Past several years, research efforts have been focused on the role of type I IFN and IFN-inducible genes in the pathogenesis of SSc. Polymorphisms in the Interferon regulatory factor (IRF)-5, IRF7, and IRF8 are associated with SSc, Similarly, polymorphism of Signal Transducer and Activator of Transcription (STAT)-4, has been established as a genetic risk factor of SSc. IRFs and STAT4 proteins are key activators of type I IFN signaling pathways. An IFN signature (increased expression and activation of IFN-regulated genes) has been observed in the peripheral blood and skin biopsy samples of patients with SSc. Furthermore, a plasma IFN-inducible chemokine score correlated with markers of disease severity and autoantibody subtypes in SSc. In this review, we summarize our current knowledge of the role of type I IFNs and IFN-inducible genes in the pathogenesis of SSc and their potential role as biomarkers and therapeutic targets.
doi:10.3389/fimmu.2013.00266
PMCID: PMC3764426  PMID: 24046769
systemic sclerosis; innate immunity; type 1 IFN; interferon regulatory factor; IFN-inducible cytokines and chemokines
4.  Anti-hnRNP B1 (RA33) Autoantibodies Are Associated with the Clinical Phenotype in Russian Patients with Rheumatoid Arthritis and Systemic Sclerosis 
Journal of Immunology Research  2014;2014:516593.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are potent autoantigenic targets in systemic autoimmune rheumatic diseases (SARD). Loss of tolerance to the RA33 complex consisting of hnRNP A2 and its alternatively spliced variants B1 and B2 has been the interest of rheumatologists. A novel ELISA for the detection of anti-hnRNP B1 autoantibodies has been developed to investigate the prevalence thereof in 397 patients with SARD, including patients with rheumatoid arthritis (RA), spondyloarthropathy (SPA), juvenile chronic arthritis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren's syndrome (SS), in comparison to 174 controls. Anti-hnRNP B1 autoantibodies were significantly more prevalent in patients with SARD than controls (47/397, 11.8% versus 2/174, 1.1%; P < 0.001). In particular, anti-hnRNP B1 were found more frequently in the disease cohorts than in the controls and were present in 24/165 (14.5%) patients with RA, 6/58 (10.3%) SPA, 11/65 (16.9%) SSc, and 4/50 (8.0%) SLE. In RA patients, anti-hnRNP B1 autoantibodies correlated significantly with C-reactive protein levels and erythrocyte sedimentation rate, while in patients with SSc it was associated with features of arterial wall stiffness and presence of hypertension. Anti-hnRNP B1 autoantibodies occur in SARD and seem to be correlated with distinct clinical characteristics in patients with RA and SSc.
doi:10.1155/2014/516593
PMCID: PMC4027001  PMID: 24883333
5.  Up regulated expression of tumour necrosis factor α converting enzyme in peripheral monocytes of patients with early systemic sclerosis 
Annals of the Rheumatic Diseases  2005;64(8):1165-1173.
Background: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems.
Objective: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor α (TNFα) converting enzyme (TACE).
Methods: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS).
Results: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3α (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14+ monocytes both in patients with SSc and controls. TACE expression on CD14+ cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016).
Conclusions: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNFα and other immunoregulatory molecules.
doi:10.1136/ard.2004.030338
PMCID: PMC1755608  PMID: 16014681
6.  Interferon and Alternative Activation of Monocyte/Macrophages in Systemic Sclerosis–Associated Pulmonary Arterial Hypertension 
Arthritis and rheumatism  2011;63(6):1718-1728.
Objective
To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)–regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc).
Methods
Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN-regulated and “PAH biomarker” genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN-regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14− and CD14+ cell populations. Interleukin-13 (IL-13) and IL-4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry.
Results
Increased PBMC expression of both IFN-regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN-regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P < 0.001) and JAK2 (P < 0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P < 0.001) and correlated strongly with pulmonary artery pressure (r = 0.52, P = 0.03) and higher mortality (P = 0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL-13. IL-13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P < 0.001).
Conclusion
IFN-regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL-13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.
doi:10.1002/art.30318
PMCID: PMC4030759  PMID: 21425123
7.  The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis 
PLoS ONE  2013;8(1):e54419.
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10−8, OR  = 1.22, CI 95%  = 1.14–1.30; rs2004640: P  = 4.60×10−7, OR  = 0.84, CI 95%  = 0.78–0.90; rs10488631: P  = 7.53×10−20, OR  = 1.63, CI 95%  = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10−22, OR  = 1.75, CI 95%  = 1.56–1.97) better explained the observed association (likelihood P-value  = 1.48×10−4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.
doi:10.1371/journal.pone.0054419
PMCID: PMC3553151  PMID: 23372721
8.  Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis☆ 
Journal of autoimmunity  2010;35(1):52-57.
Objective
To determine aggregation of autoimmune diseases in the first degree relatives (FDR) of patients with systemic sclerosis (SSc) and to investigate frequencies of antinuclear antibodies (ANA) and other autoantibodies in the FDRs and spouses of patients with SSc.
Methods
Information on FDRs including history of autoimmune disease was obtained from unrelated SSc probands in the Scleroderma Family Registry and DNA Repository. FDRs were contacted to verify any reported autoimmune diseases. The prevalence of autoimmune disease in probands’ families was compared with the corresponding prevalence in controls’ families as reported in the literature. Furthermore, sera from probands’ FDRs and spouses in addition to unrelated controls were investigated for the presence of autoantibodies (ANA).
Results
We investigated 4612 FDRs of 1071 SSc probands. SSc probands with anti-centromere antibodies (ACA) and limited disease type were more likely to report familial autoimmunity (p = 0.022 and p = 0.041, respectively). The four most prevalent autoimmune diseases among SSc probands’ FDRs were hypothyroidism (4%), Rheumatoid arthritis (1.5%), hyperthyroidism (1.3%) and systemic lupus erythematosus-SLE (0.4%). Compared to control families, SLE, hypothyroidism and hyperthyroidism were more common in SSc probands’ families. The most striking increase for familial prevalence was observed in SLE (OR = 16.98, 95% CI = 1.02–227.82, p = 0.004). ANA was present in 14.2% of probands’ FDR’s and 8.6% of spouses and did not differ from the prevalence of ANA among controls (p = 0.124 and p = 0.477, respectively). Only two FDRs of probands had ACA while none had anti-topoisomerase antibodies.
Conclusion
Our study implies varying degrees of risk for familial autoimmunity among subtypes of SSc and provides further support for common genetic and potentially environmental factors leading to SSc and SLE.
doi:10.1016/j.jaut.2010.02.001
PMCID: PMC2878866  PMID: 20223638
Systemic sclerosis; Scleroderma; First degree relatives; ANA; Autoimmune disease
9.  Clinical and serological evaluation of a novel CENP-A peptide based ELISA 
Introduction
Anti-centromere antibodies (ACA) are useful biomarkers in the diagnosis of systemic sclerosis (SSc). ACA are found in 20 to 40% of SSc patients and, albeit with lower prevalence, in patients with other systemic autoimmune rheumatic diseases. Historically, ACA were detected by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed by immunoassays using recombinant CENP-B. The objective of this study was to evaluate a novel CENP-A peptide ELISA.
Methods
Sera collected from SSc patients (n = 334) and various other diseases (n = 619) and from healthy controls (n = 175) were tested for anti-CENP-A antibodies by the novel CENP-A enzyme linked immunosorbent assay (ELISA). Furthermore, ACA were determined in the disease cohorts by IIF (ImmunoConcepts, Sacramento, CA, USA), CENP-B ELISA (Dr. Fooke), EliA® CENP (Phadia, Freiburg, Germany) and line-immunoassay (LIA, Mikrogen, Neuried, Germany). Serological and clinical associations of anti-CENP-A with other autoantibodies were conducted in one participating centre. Inhibition experiments with either the CENP-A peptide or recombinant CENP-B were carried out to analyse the specificity of anti-CENP-A and -B antibodies.
Results
The CENP-A ELISA results were in good agreement with other ACA detection methods. According to the kappa method, the qualitative agreements were: 0.73 (vs. IIF), 0.81 (vs. LIA), 0.86 (vs. CENP-B ELISA) and 0.97 (vs. EliA® CENP). The quantitative comparison between CENP-A and CENP-B ELISA using 265 samples revealed a correlation value of rho = 0.5 (by Spearman equation). The receiver operating characteristic analysis indicated that the discrimination between SSc patients (n = 131) and various controls (n = 134) was significantly better using the CENP-A as compared to CENP-B ELISA (P < 0.0001). Modified Rodnan skin score was significantly lower in the CENP-A negative group compared to the positive patients (P = 0.013). Inhibition experiments revealed no significant cross reactivity of anti-CENP-A and anti-CENP-B antibodies. Statistically relevant differences for gender ratio (P = 0.0103), specific joint involvement (Jaccoud) (P = 0.0006) and anti-phospholipid syndrome (P = 0.0157) between ACA positive SLE patients and the entire SLE cohort were observed.
Conclusions
Anti-CENP-A antibodies as determined by peptide ELISA represent a sensitive, specific and independent marker for the detection of ACA and are useful biomarkers for the diagnosis of SSc. Our data suggest that anti-CENP-A antibodies are a more specific biomarker for SSc than antibodies to CENP-B. Furthers studies are required to verify these findings.
doi:10.1186/ar3029
PMCID: PMC2911886  PMID: 20487535
10.  Polymorphism of immunoglobulin enhancer element HS1,2A: allele *2 associates with systemic sclerosis. Comparison with HLA‐DR and DQ allele frequency 
Annals of the Rheumatic Diseases  2007;66(9):1210-1215.
Objective
To investigate the relationship of the polymorphic enhancer HS1,2 central to the 3′ enhancer complex regulatory region (IgH3′EC) of the immunoglobulin heavy chain genes with systemic sclerosis (SSc) disease and compare it with HLA‐DR and DQ associations.
Methods
A total of 116 patients with SSc were classified as diffuse (dSSc) or limited (lSSc), and as carriers of antitopoisomerase I (anti‐Scl70) or anticentromere (ACA) antibodies. Allele and genotype frequencies were assessed in the population as a whole and in the two major subsets, dSSc and lSSc. The concentration of peripheral blood immunoglobulin levels was also determined and analysed according to the genotypes.
Results
The analysis of genotypes for the four alleles of the HS1,2A enhancer showed an increased frequency of allele *2 in the SSc cohort highly significant versus controls (57% vs. 40%, p<0.0001). Considering the autoantibody pattern, we found that the frequency of the 2/2 genotype was increased in ACA+ patients (42%) and anti‐Scl70+ patients (31%) compared with the control group (15%). The differences of allelic frequencies among dSSc versus lSSc or ACA+ versus anti‐Scl70+ patients were not significant, although highly significant when comparing each subgroup with the control group. HLA‐DRB1*11 and DQB1*03 associated with SSc. No association was seen between HS1,2A enhancer polymorphism and HLA alleles.
Conclusions
These data confirm there was an increased risk of having SSc in carriers of allele *2, suggesting an intriguing function of this polymorphism for B‐cell regulation.
doi:10.1136/ard.2006.066597
PMCID: PMC1955163  PMID: 17392350
11.  Clinical and serological features of systemic sclerosis in a Chinese cohort 
Clinical rheumatology  2012;32(5):617-621.
Our goal was to study the prevalence of systemic sclerosis (SSc) subtypes, autoantibody profile, and pulmonary fibrosis in a large group of Han Chinese. Chinese SSc patients (n=419) were recruited from a multicenter study including hospitals and outpatient clinics in China. All patients met the American College of Rheumatology classification criteria for SSc. Anti-topoisomerase (ATA), anti-centromere (ACA), anti- RNA polymerase III (anti-RNAP3), and anti-U1- ribonucleoprotein (anti-U1RNP) were detected utilizing commercially available kits. The clinical and autoantibody information in Chinese patients was compared to that in the US Caucasian patients (n=834), recruited from the Genetics versus Environment in Scleroderma Outcome Study and Scleroderma Family Registry. Chi-square test was utilized for the abovementioned comparisons. Chinese patients showed 40.3 % limited (lcSSc) and 59.7 % diffuse (dcSSc) forms of SSc. ATA was found in 59.9 %, ACA in 13.4 %, anti-RNAP3 in 1.3 %, and anti-U1RNP in 18 % of Chinese SSc patients. Compared to US patients (65.1 % lcSSc, 34.9 % dcSSc, ATA in 18.7 %, ACA in 32.4 %, anti-RNAP3 in 17.4 %, and anti-U1RNP in 2.8 %), Chinese SSc patients are significantly higher in dcSSc and the frequencies of ATA and anti-U1RNP, but lower in ACA and anti-RNAP3. In addition, pulmonary fibrosis was observed in 78 % Chinese SSc patients and was strongly associated with the presence of ATA. The present study represents the first report of SSc features in a large group of Chinese patients. Clinical subtypes and the frequencies of SSc-related autoantibodies in Chinese SSc patients are significantly different from those in SSc patients of the US Caucasian descent.
doi:10.1007/s10067-012-2145-7
PMCID: PMC3734856  PMID: 23271609
Anti-centromere antibody; Anti-topoisomerase antibody; Autoantibodies; Pulmonary fibrosis; Systemic sclerosis
12.  Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis 
The Journal of rheumatology  2012;39(5):997-1003.
Objective
Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.
Methods
Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.
Results
Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intracohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)].
Conclusion
We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype. (First Release March 15 2012; J Rheumatol 2012;39:997–1003; doi:10.3899/jrheum.111270)
doi:10.3899/jrheum.111270
PMCID: PMC3687343  PMID: 22422496
SYSTEMIC SCLEROSIS; TNFSF4; AUTOIMMUNITY; AUTOANTIBODIES
13.  Work Disability in Scleroderma is Greater than in Rheumatoid Arthritis and is Predicted by High HAQ Scores 
Objectives
To estimate the frequency of work disability (WD) in a cohort of patients with Systemic Sclerosis (SSc) vs an internal control group of patients with rheumatoid arthritis (RA) with a known high frequency of WD; and to investigate the association between WD and other factors including Health Assessment Questionnaire Disability Index (HAQ-DI) scores, HAQ pain, age, sex, disease duration and education level.
Methods
Cross-sectional data on WD status were obtained from a questionnaire sent to all SSc (n = 35 limited [lcSSc], 26 diffuse [dcSSc]) and a subset of RA patients (n=104) from a rheumatology practice. WD data, HAQ-DI scores, and demographic/clinical features (age, sex, high school education, disease duration and SSc disease subtype [dcSSc vs lcSSc]) were recorded.
Results
The proportion with WD was 0.56 in SSc (95% CI: 0.43-0.68) vs 0.35 in RA (95% CI: 0.25-0.44), p= 0.009. HAQ-DI scores were significantly higher in work-disabled SSc and RA patients vs those who were employed (p=0.0001, and p <0.0001). Multivariate logistic regression analysis demonstrated that higher HAQ-DI scores (β=1.78, p <0.001), disease type (dcSSc, lcSSc, RA) (β=1.32 for dcSSc, p=0.032), and self-reported disease duration (β=0.04, p=0.042) were significantly associated with WD (R2=0.311). Adding a work-related factor (self-reported physically demanding work) improved the regression model (R2=0.346) and strengthened the HAQ-DI (β=1.86, p <0.001) and lcSSc (β=1.24, p=0.024) coefficients.
Conclusion
The frequency of WD in SSc was high and was greater than in RA. SSc (and dcSSc) had significantly more WD than RA. The HAQ-DI was strongly associated with WD in SSc
doi:10.2174/1874312900802010044
PMCID: PMC2588092  PMID: 19088871
Scleroderma; systemic sclerosis; work disability; health assessment questionnaire
14.  Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis 
Annals of the Rheumatic Diseases  2010;69(3):550-555.
Objective
It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
Methods
A total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.
Results
Case-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.
Conclusions
Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.
doi:10.1136/ard.2009.116434
PMCID: PMC2927683  PMID: 19778912
15.  Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma 
Introduction
We assessed the profile and frequency of malignancy subtypes in a large single-centre UK cohort for patients with scleroderma (systemic sclerosis; SSc). We evaluated the cancer risk among SSc patients with different antibody reactivities and explored the temporal association of cancer with the duration between SSc onset and cancer diagnosis.
Methods
We conducted a retrospective study of a well-characterised cohort of SSc patients attending a large tertiary referral centre, with clinical data collected from our clinical database and by review of patient records. We evaluated development of all cancers in this cohort, and comparison was assessed with the SSc cohort without cancer. The effect of demographics and clinical details, including antibody reactivities, were explored to find associations relevant to the risk for development of cancer in SSc patients.
Results
Among 2,177 patients with SSc, 7.1% had a history of cancer, 26% were positive for anticentromere antibodies (ACAs), 18.2% were positive for anti-Scl-70 antibodies and 26.6% were positive for anti-RNA polymerase III (anti-RNAP) antibody. The major malignancy cancer subtypes were breast (42.2%), haematological (12.3%), gastrointestinal (11.0%) and gynaecological (11.0%). The frequency of cancers among patients with RNAP (14.2%) was significantly increased compared with those with anti-Scl-70 antibodies (6.3%) and ACAs (6.8%) (P < 0.0001 and P < 0.001, respectively). Among the patients, who were diagnosed with cancer within 36 months of the clinical onset of SSc, there were more patients with RNAP (55.3%) than those with other autoantibody specificities (ACA = 23.5%, P < 0.008; and anti-Scl-70 antibodies = 13.6%, P < 0.002, respectively). Breast cancers were temporally associated with onset of SSc among patients with anti-RNAP, and SSc patients with anti-RNAP had a twofold increased hazard ratio for cancers compared to patients with ACAs (P < 0.0001).
Conclusions
Our study independently confirms, in what is to the best of our knowledge the largest population examined to date, that there is an association with cancer among SSc patients with anti-RNAP antibodies in close temporal relationship to onset of SSc, which supports the paraneoplastic phenomenon in this subset of SSc cases. An index of cautious suspicion should be maintained in these cases, and investigations for underlying malignancy should be considered when clinically appropriate.
doi:10.1186/ar4486
PMCID: PMC3978927  PMID: 24524733
16.  Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis 
Annals of the Rheumatic Diseases  2011;71(1):114-119.
Objective
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.
Methods
Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc.
Results
Four out of five analysed SNPs were Significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: pFDR=6.14 × 10−4, OR=0.78; rs4963128: pFDR=6.14 × 10−4, OR=0.79; rs702966: pFDR=3.83 × 10−3, OR=0.82; and rs2246614: pFDR=3.83 × 10−3, OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant.
Conclusions
The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.
doi:10.1136/annrheumdis-2011-200275
PMCID: PMC3369428  PMID: 21926187
17.  Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls 
Annals of the Rheumatic Diseases  2001;60(9):846-851.
BACKGROUND—Excess tissue matrix accumulates in systemic sclerosis (SSc), accounting for both visceral and dermal fibrosis. It is suggested that decreased serum levels of matrix metalloproteinases (MMPs) or increased levels of tissue inhibitors of matrix metalloproteinases (TIMPs) may account for this matrix accumulation.
OBJECTIVE—To measure serum levels of tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and collagenase-1 (MMP-1), in patients with diffuse cutaneous systemic sclerosis (dcSSc), limited cutaneous systemic sclerosis (lcSSc), primary Raynaud's phenomenon (RP), and in normal controls.
METHODS—Serum samples from patients with dcSSc (n=83), lcSSc (n=87), RP (n=80), and normal controls (n=98) were analysed using enzyme linked immunosorbent assays (ELISAs) for total TIMP-1, TIMP-2, and MMP-1. Results from each assay were analysed by the Kruskal-Wallis test. Dunn's multiple comparison post-test was then applied between groups.
RESULTS—TIMP-1 levels were significantly raised in dcSSc and lcSSc groups compared with the RP group and normal controls (p<0.01 to p<0.001). In the dcSSc group, TIMP-1 levels were significantly higher in early disease (<2 years) than in late stage disease (>4 years) (p<0.05). This was not found for the lcSSc group. Serum TIMP-2 and MMP-1 levels in dcSSc and lcSSc did not differ significantly from those in normal controls. Increased levels of TIMPs were not convincingly associated with organ disease. No assay result correlated with autoantibody status (anti-topoisomerase 1 (anti-Scl-70), anticentromere antibody, or anti-RNA polymerase). No significant differences in serum TIMP-1, TIMP-2, or MMP-1 levels were shown in the RP group compared with normal controls.
CONCLUSIONS—Raised TIMP-1 levels in the SSc groups support the hypothesis that matrix accumulation occurs in SSc at least in part owing to decreased degradation. Moreover, the variation in TIMP-1 levels between the early and late disease stages of dcSSc seems to reflect the early progressive course of dermal fibrosis seen clinically. The expected reduction in serum MMP-1 levels in the SSc groups was not found. This suggests that tissue matrix accumulation is due to increased inhibitors rather than to decreased MMPs.


PMCID: PMC1753839  PMID: 11502611
18.  Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus 
To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.
doi:10.4061/2009/374312
PMCID: PMC2950308  PMID: 20948567
19.  Constitutive Phosphorylation of Interferon Receptor A-Associated Signaling Proteins in Systemic Lupus Erythematosus 
PLoS ONE  2012;7(7):e41414.
Background
Overexpression of type I interferon (IFN-I)-induced genes is a common feature of systemic lupus erythematosus (SLE) and its experimental models, but the participation of endogenous overproduction of IFN-I on it is not clear. To explore the possibility that abnormally increased IFN-I receptor (IFNAR) signaling could participate in IFN-I-induced gene overexpression of SLE, we examined the phosphorylation status of the IFNAR-associated signaling partners Jak1 and STAT2, and its relation with expression of its physiologic inhibitor SOCS1 and with plasma levels of IFNα and IFN-like activity.
Methodology/Principal Findings
Peripheral blood mononuclear cells (PBMC) from SLE patients with or without disease activity and healthy controls cultured in the presence or in the absence of IFNβ were examined by immunoprecipitation and/or western blotting for expression of the two IFNAR chains, Jak1, Tyk2, and STAT2 and their phosphorylated forms. In SLE but not in healthy control PBMC, Jak1 and STAT2 were constitutively phosphorylated, even in the absence of disease activity (basal pJak1: controls vs. active SLE p<0.0001 and controls vs. inactive SLE p = 0.0006; basal pSTAT2: controls vs. active and inactive SLE p<0.0001). Although SOCS1 protein was slightly but significantly decreased in SLE in the absence or in the presence of IFNβ (p = 0.0096 to p<0.0001), in SOCS1 mRNA levels were markedly decreased (p = 0.036 to p<0.0001). IFNβ induced higher levels of the IFN-I-dependent MxA protein mRNA in SLE than in healthy controls, whereas the opposite was observed for SOCS1. Although there was no relation to increased serum IFNα, active SLE plasma could induce expression of IFN-dependent genes by normal PBMC.
Conclusions/Significance
These findings suggest that in some SLE patients IFN-I dependent gene expression could be the result of a low IFNAR signaling threshold.
doi:10.1371/journal.pone.0041414
PMCID: PMC3408474  PMID: 22859983
20.  Clinical correlates of a subset of anti-CENP-A antibodies cross-reacting with FOXE3p53-62 in systemic sclerosis 
Introduction
In a subset of patients with limited cutaneous (lc) systemic sclerosis (SSc), anti-CENP-A antibodies (Ab) cross-react with a peptide (FOXE3p53-62) that presents striking homology with one of the two immunodominant epitopes of CENP-A (Ap17-30). We searched for clinical correlates of anti-FOXE3p53-62 Ab by measuring their levels along with those of Ab to Ap17-30 and to the second immunodominant epitope of CENP-A, namely Ap1-17.
Methods
Serum samples were obtained from 121 patients with SSc, 46 patients with systemic lupus erythematosus (SLE) and 25 healthy blood donors (HBD). The reactivity of serum IgG to Ap1-17, Ap17-30 and FOXE3p53-62 was measured by ELISA. The corresponding anti-peptide Ab were affinity-purified from pooled SSc sera and used to establish standard curves for quantifying these Ab in patients and HBD. Receiver operating characteristics (ROC) analysis, comparing SSc patients who were positive for anti-CENP Ab (ACA+) to those who were negative, was used to find cut-off points for dichotomizing the anti-peptide Ab levels into positive and negative. Clinical records were reviewed to extract demographic data and information about organ involvement and disease activity.
Results
Of 121 SSc sera, 75 were ACA+; 88.0% of these samples reacted with Ap1-17, 82.6% with Ap17-30 and 53.3% with FOXE3p53-62. Among the 46 ACA- SSc sera, 2.2% reacted with Ap1-17, 4.3% with Ap17-30 and 11% with FOXE3p53-62. The levels of these Ab were low in ACA-, SLE and HBD groups and not significantly different among them. When ACA+ SSc patients were divided into subgroups positive or negative for anti-FOXE3p53-62 Ab, the only variables that were significantly different between groups were the levels of anti-Ap17-30 Ab and disease activity index (DAI). There was a significant association between negativity for anti-FOXE3p53-62 Ab and active disease defined as either DAI ≥3 (Fisher exact test, P = 0.045) or less restrictive DAI≥2.5 (P = 0.009).
Conclusions
ACA+-Anti-FOXE3p53-62+Ab identifies a subgroup of patients with lcSSc who are less likely to develop active disease. In lc SSc patients at presentation, anti-FOXE3p53-62+ can be a marker with prognostic significance.
doi:10.1186/ar4249
PMCID: PMC3978846  PMID: 23837651
Systemic sclerosis; CENP-A; peptide; FOXE-3; disease activity index
21.  L-selectin and Skin Damage in Systemic Sclerosis 
PLoS ONE  2012;7(9):e44814.
Background
L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte-leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form. Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc). This preliminary study seeks to discern amongst these disparate results and to discover whether there is an association between L-selectin concentrations in plasma and skin damage in SSc patients.
Methodology and Principal Findings
Nineteen cases with limited systemic sclerosis (lSSc) and 11 cases with diffuse systemic sclerosis (dSSc) were compared on a pairwise basis to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to diagnose SSc. Skin involvement was assessed using the modified Rodnan skin score (mRSS). We find no association between mRSS and plasma L-selectin concentration in lSSc cases (p = 0.9944) but a statistically significant negative correlation in dSSc cases (R2 = 73.11 per cent, p = 0.0008). The interpretation of the slope for dSSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration, the mRSS drops 4.22 (95 per cent CI: 2.29, 6.16). There was also a highly statistically significant negative correlation between sL-selectin and disease activity (p = 0.0007) and severity (p = 0.0007) in dSSc cases but not in lSSc cases (p = 0.2596, p = 0.7575, respectively).
Conclusions and Significance
No effective treatments exist for skin damage in SSc patients. Nor is there a laboratory alternative to the modified Rodnan skin score as is the case for other organs within the body. Modulation of circulating L-selectin is a promising target for reducing skin damage in dSSc patients. Plasma levels of soluble L-selectin could serve as an outcome measure for dSSc patients in clinical trials.
doi:10.1371/journal.pone.0044814
PMCID: PMC3441480  PMID: 23028631
22.  Increased expression of endoplasmic reticulum stress genes in patients with limited cutaneous Systemic Sclerosis and Pulmonary Arterial Hypertension 
Arthritis and rheumatism  2013;65(5):1357-1366.
Objective
Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress/UPR are present in PBMCs from lcSSc-PAH patients.
Methods
PBMCs were purified from healthy controls (HC, n=36) and lcSSc patients, with and without PAH (lcSSc-PAH, n=32; lcSSc-NoPAH, n=34). Gene expression in HC PBMCs stimulated with thapsigargin (TG) was analyzed by DNA microarray. Genes were validated by qPCR in HC and lcSSc PBMCs.
Results
Several ER stress/UPR genes, including Immunoglobulin-heavy-chain binding protein (BiP), Activating Transcription Factor-4 and -6 (ATF4 and ATF6) and a spliced form of X-box binding protein (XBP1) were upregulated in lcSSc PBMCs, with the highest levels in patients with PAH. TG upregulated Heat shock proteins (HSP) and Interferon-regulated genes in control PBMCs. Selected HSP genes, particularly DNAJB1, and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IRF4 was significantly decreased. There was a positive correlation between DNAJB1 and severity of PAH disease (PAP) (r = 0.56, p<0.05) and between ER stress markers and IL-6 levels (r = 0.53, p< 0.0001) in lcSSc PBMCs.
Conclusion
This study demonstrates association between select ER stress/UPR markers and lcSSc-PAH suggesting that ER stress/UPR may contribute to the altered function of circulating immune cells in lcSSc.
doi:10.1002/art.37891
PMCID: PMC3636187  PMID: 23400395
23.  Association of Interleukin 23 Receptor Polymorphisms with Anti-Topoisomerase-I Positivity and Pulmonary Hypertension in Systemic Sclerosis 
The Journal of rheumatology  2009;36(12):2715-2723.
Objective
IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
Methods
We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease.
Results
Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3×10−5, p = 1×10−5, respectively).
Conclusion
Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.
doi:10.3899/jrheum.090421
PMCID: PMC2895677  PMID: 19918037
SYSTEMIC SCLEROSIS; SCLERODERMA; IL23R; POLYMORPHISM; AUTOANTIBODIES; PULMONARY HYPERTENSION
24.  Membrane diffusion- and capillary blood volume measurements are not useful as screening tools for pulmonary arterial hypertension in systemic sclerosis: a case control study 
Respiratory Research  2008;9(1):68.
Background
There is no optimal screening tool for the assessment of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc). A decreasing transfer factor of the lung for CO (TLCO) is associated with the development of PAH in SSc. TLCO can be partitioned into the diffusion of the alveolar capillary membrane (Dm) and the capillary blood volume (Vc). The use of the partitioned diffusion to detect PAH in SSc is not well established yet. This study evaluates whether Dm and Vc could be candidates for further study of the use for screening for PAH in SSc.
Methods
Eleven SSc patients with PAH (SScPAH+), 13 SSc patients without PAH (SScPAH-) and 10 healthy control subjects were included. Pulmonary function testing took place at diagnosis of PAH. TLCO was partitioned according to Roughton and Forster. As pulmonary fibrosis in SSc influences values of the (partitioned) TLCO, these were adjusted for fibrosis score as assessed on HRCT.
Results
TLCO as percentage of predicted (%) was lower in SScPAH+ than in SScPAH- (41 ± 7% vs. 63 ± 12%, p < 0.0001, respectively). Dm% in SScPAH+ was decreased as compared with SScPAH- (22 ± 6% vs. 39 ± 12%, p < 0.0001, respectively), also after adjustment for total fibrosis score (before adjustment: B = 17.5, 95% CI 9.0–25.9, p = < 0.0001; after adjustment: B = 14.3, 95% CI 6.0–21.7, p = 0.008). No difference was found in Vc%. There were no correlations between pulmonary hemodynamic parameters and Dm% in the PAH groups.
Conclusion
SScPAH+ patients have lower Dm% than SScPAH- patients. There are no correlations between Dm% and hemodynamic parameters of PAH in SScPAH+. These findings do not support further study of the role of partitioning TLCO in the diagnostic work- up for PAH in SSc.
doi:10.1186/1465-9921-9-68
PMCID: PMC2576177  PMID: 18828919
25.  Elevated Serum Levels of Interferon-Regulated Chemokines Are Biomarkers for Active Human Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e491.
Background
Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role for type I interferon (IFN) in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity.
Methods and Findings
We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity.
Conclusions
These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus.
A comprehensive survey of the serologic proteome in human SLE suggests that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed.
Editors' Summary
Background.
The term “lupus,” meaning wolf in Latin, is often used as an abbreviation for the disease systemic lupus erythematosus (SLE). The name may have been given because some people with SLE have a rash that slightly resembles a wolf's face. The condition affects around 50 to 100 people per 100,000, and is much more common in women than men. SLE is a complicated disease that comes about when antibodies inappropriately attack the body's own connective tissues, although it is not known why this happens. Symptoms vary between different people; the disease may get better and then worse, without explanation; and can affect many different organs including the skin, joints, kidneys, blood cells, and brain and nervous system. SLE is difficult for doctors to diagnose. Although the disease cannot be cured, patients who are diagnosed with SLE can be treated for their symptoms, and the right management can slow progress of the disease. One area of SLE research focuses on finding “molecular markers” (e.g., proteins or other compounds) that could be tested for in the blood. Researchers hope this would help doctors to more accurately diagnose SLE initially, and then also help to track progress in a patient's condition.
Why Was This Study Done?
“Gene expression” is a term meaning the process by which a gene's DNA sequence is converted into the structures and functions of a cell. These investigators had found in previous studies that certain genes were more “highly expressed” in the blood cells of patients with SLE. Some of these genes were already known to be regulated by interferons (a group of proteins, produced by certain blood cells, that are important in helping to defend against viral infections). The investigators performing this study wanted to understand more clearly the role of interferon in SLE and to see whether the genes that are more highly expressed in patients with SLE go on to produce higher levels of protein, which might then provide useful markers for monitoring the condition.
What Did the Researchers Do and Find?
This research project was a “case-control” study, in which the researchers compared the levels of certain proteins in the blood of people who had SLE with the levels in people who did not have the condition. Thirty people were recruited as cases, from a group of patients with SLE who have been under evaluation at Johns Hopkins School of Medicine since 1987. Fifteen controls were recruited from a group of healthy people of similar age and sex as the patients with SLE; everyone involved in the study gave their consent to take part. Blood samples were taken from each individual, and the serum (liquid component of blood) was separated out. The serum levels of 160 different blood proteins were then measured. When comparing levels of blood proteins between the groups, the researchers found that 30 specific proteins were present at higher or lower levels in the SLE-affected patients. Many of these proteins are cytokines, which are regulated by interferons and are involved in the process of “signaling” within the immune system. A few proteins were found at lower levels. Levels of the interferon-regulated proteins were, on average, seen at higher levels in people whose condition was more severe.
What Do These Findings Mean?
These results suggest that patients with SLE are likely to have a very different pattern of regulation of certain proteins within the blood, particularly the proteins involved in signaling within the immune system. The authors propose that these proteins may be involved in the progression of the disease. There is also the possibility that some of these proteins may prove useful in diagnostic tests, or in tests for monitoring how the disease progresses. However, before any such tests could be used in clinical practice, they would need to be further developed and then thoroughly tested in clinical trials.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030491
Patient information from the UK National Health Service on systemic lupus erythematosus
Patient handout from the US National Institutes of Health
MedlinePLUS encyclopedia entry on lupus
Information on lupus from the UK Arthritis Research Campaign
doi:10.1371/journal.pmed.0030491
PMCID: PMC1702557  PMID: 17177599

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