Tumor necrosis factor-α (TNF-α) 308 G/A gene polymorphism has been reported to be associated with susceptibility to silicosis. However, the relevant study results are still inconsistent.
Objective and Methods
A meta-analysis was performed in order to drive a more precise estimation of the relationship between TNF-α-308 G/A gene polymorphism and susceptibility to silicosis. Electronic databases were searched and nine separate studies were included. The pooled odds ratios (ORs) and the corresponding 95% confidence internal (CI) were calculated by a fixed effect model.
A total of 1267 cases and 1214 controls were included. In the overall analysis, significantly increased silicosis risk was found (for GA+AA vs. GG OR=1.45, 95%CI: 1.20-1.760, P=1.58E4; for GA vs. GG: OR=1.53, 95%CI=1.25-1.86, P=3.11E5; for A allele vs. G allele: OR=1.27, 95%CI=1.08-1.50, P= 0.004). In the subgroup analysis, significantly increased silicosis risk was also found among Asians (for GA+AA vs. GG: OR=1.63, 95%CI=1.27-2.08, P=1.01E4), for GA vs. GG: OR=1.71, 95%CI=1.33-2.20, P=3.44E5), for A allele vs. G allele: OR=1.45, 95%CI=1.17-1.80, P=0.001). However, no significantly increased risk was found among non-Asians for all genetic models.
TNF-α-308 G/A polymorphism might lead to an increased risk of silicosis susceptibility, especially for Asians. However, further studies with large sample sizes should be conducted to confirm the association.
Knee range of motion (KROM) is associated with the ability to perform daily activities in people with knee OA. However, this association is weak, possibly through the use of linear analyses. Curvilinear associations appear much more relevant, as these allow the determination of relevant clinical thresholds in KROM. The goal of this study is to assess the curvilinear association between KROM and daily activities (self-reported and observed) in people with knee osteoarthritis (OA).
Demographic, functional and KROM (flexion and extension) data were collected from a convenience sample of people with knee OA awaiting total knee arthroplasty. Self-reported functioning was measured by use of the Knee Osteoarthritis Outcomes Scale and observed functioning with the timed up and go and six-minute walk test. The presence of curvilinear relationships between KROM and measures of functioning were tested by generalized additive modeling, piecewise regression modeling and receiver operated curves.
Data from 110 participants (mean age ± standard deviation: 65 ± 9 and female: 54%) with knee OA were evaluated. Statistical modeling did not reveal linear nor curvilinear associations between KROM and self-reported or observed measures of functioning; except for statistical significant associations between reduced knee flexion and major difficulties standing (p<=0.01). However, further modeling did not provide convincing evidence for relevant clinical associations and thresholds.
No clinically relevant relationship between KROM and self-reported or observed measures of physical functioning could be established, indicating that the limitations in range of motion in the affected knee OA alone do not contribute to poorer functional performance.
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.
Anti-centromere antibody; Anti-topoisomerase antibody; Autoantibodies; Pulmonary fibrosis; Systemic sclerosis
Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN.
Methods and analysis
SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500–2000 patients from centres across the world within a period of 5 years (2013–2018). Eligible participants are persons ≥18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once interventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions.
Ethics and dissemination
The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc.
Rheumatology; Statistics & Research Methods; Rehabilitation Medicine; Mental Health
The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.
The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study.
Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%.
Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant.
An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.
Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue;
influenced by genetic and environmental components. Recently, we performed the first
successful genome-wide association study (GWAS) of SSc. Here, we perform a large
replication study to better dissect the genetic component of SSc. We selected 768
polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from
Europe. Overall significance was calculated for replicated significant SNPs by
meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097
controls). Six SNPs in regions not previously associated with SSc were selected for
validation in another five independent cohorts, up to a total of 5270 SSc patients and
8326 controls. We found evidence for replication and overall genome-wide significance for
one novel SSc genetic risk locus: CSK [P-value =
5.04 × 10−12, odds ratio (OR) = 1.20]. Additionally, we
found suggestive association in the loci PSD3 (P-value
= 3.18 × 10−7, OR = 1.36) and
NFKB1 (P-value = 1.03 ×
10−6, OR = 1.14). Additionally, we strengthened the evidence
for previously confirmed associations. This study significantly increases the number of
known putative genetic risk factors for SSc, including the genes CSK,
PSD3 and NFKB1, and further confirms six previously
To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc).
Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests.
Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003).
Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.
GASTRIC ANTRAL VASCULAR ECTASIA; GAVE; SYSTEMIC SCLEROSIS VASCULOPATHY; ENDOSCOPY
Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants.
Overall, 502 AS patients were examined, consisting of 312 who had first-degree relatives (FDR) with AS (familial) and 190 who had no FDR with AS or spondyloarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York Criteria for AS. The patients were recruited from two U.S. cohorts (NASC and PSOAS) and from the United Kingdom- Oxford cohort. The frequencies of AS susceptibility loci in IL23R, IL1R2, ANTRX2, ERAP1, two intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag SNP rs4349859 were compared between familial and sporadic cases. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size.
HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (p=0.0001, OR: 4.44, CI: (2.06–9.55)). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend towards higher frequency in the multiplex cases (p=0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined.
HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-MHC susceptibility loci is not markedly different between the sporadic and familial cases of AS.
A single-nucleotide polymorphism (SNP) at the IL12RB2 locus
showed a suggestive association signal in a previously published genome-wide
association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the
possible implication of the IL12RB2 gene in SSc, we conducted a
follow-up study of this locus in different Caucasian cohorts.
We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309
SSc patients and 5161 controls). We then selected three SNPs (rs3790567,
rs3790566 and rs924080) based on their significance level in the GWAS, for
follow-up in an independent European cohort comprising 3344 SSc and 3848
controls. The most-associated SNP (rs3790567) was further tested in an
independent cohort comprising 597 SSc patients and 1139 controls from the USA.
After conditional logistic regression analysis of the GWAS data, we selected
rs3790567 [PMH= 1.92 ×
10−5 odds ratio (OR) = 1.19] as the genetic variant
with the firmest independent association observed in the analyzed GWAS peak of
association. After the first follow-up phase, only the association of rs3790567
was consistent (PMH= 4.84 ×
10−3 OR = 1.12). The second follow-up phase
confirmed this finding (Pχ2 = 2.82
× 10−4 OR = 1.34). After performing overall
pooled-analysis of all the cohorts included in the present study, the
association found for the rs3790567 SNP in the IL12RB2 gene
region reached GWAS-level significant association
(PMH= 2.82 ×
10−9 OR = 1.17). Our data clearly support the
IL12RB2 genetic association with SSc, and suggest a
relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
Significant advances have been made in understanding the genetic basis of systemic sclerosis (scleroderma) in recent years. Can these discoveries lead to individualized monitoring and treatment? Besides robustly replicated genetic susceptibility loci, several genes have been recently linked to various systemic sclerosis disease manifestations. Furthermore, inclusion of genetic studies in design and analysis of drug trials could lead to development of genetic biomarkers that predict treatment response. Future genetic studies in well-characterized systemic sclerosis cohorts paired with advanced analytic approaches can lead to development of genetic biomarkers for targeted diagnostic and therapeutic interventions in systemic sclerosis.
systemic sclerosis; scleroderma; genetic; biomarker; severity
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.
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.
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.
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.
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.
systemic sclerosis; innate immunity; type 1 IFN; interferon regulatory factor; IFN-inducible cytokines and chemokines
Human leucocyte antigen (HLA) B*27 is a susceptibility allele to ankylosing spondylitis (AS). However, major AS-associated subtypes of HLA-B*27 and other HLA-B alleles vary in different ethnic populations. Herein, we examined HLA-B alleles in a total of 360 AS patients and 350 controls of Chinese Han ancestry. The HLA-B genotyping was performed with sequence-based typing (SBT) method. Six HLA-B*27 subtypes B*27:04, B*27:05, B*27:07, B*27:08, B*27:10 and B*27:15 were observed in the cohorts. HLA-B*27:04:01 and -B*27:05:02 appeared significantly increased in AS patients, which indicated as two major susceptibility alleles to AS. Homozygous B*27 was observed only in AS patients. There are 30 HLA-B alleles identified in the studies. HLA-B*15, especially B*15:01:01:01, appeared as the major allele type in the Chinese controls. Some common HLA-B alleles such as HLA-B*15, B*13, B*46 and B*51 were significantly reduced in Chinese AS patients. In conclusion, the studies profiled the HLA-B alleles, and identified major susceptibility subtypes of B27 to AS in Han Chinese population
Ankylosing spondylitis (AS); HLA-B27; Chinese Han.
Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Herein, we determined if OPN levels are increased in a large cohort of systemic sclerosis (SSc) patients and if OPN contributes dermal fibrosis. Plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared to healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin-induced dermal fibrosis model. OPN deficient (OPN−/−) mice developed less dermal fibrosis compared to wild-type mice in the bleomycin-induced dermal fibrosis model. Additional in vivo studies demonstrated that lesional skin from OPN−/− mice had fewer Mac-3+ cells, fewer myofibroblasts, decreased TGF-beta (TGFβ) and genes in the TGFβ pathway and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and ERK. In vitro, OPN−/− dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGFβ. Finally, TGFβ production by OPN deficient macrophages was reduced compared to wild type. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that OPN may be a novel therapeutic target in SSc.
Objectives. To explore whether helplessness, internality and depression would mediate the relationship between disease activity and functional limitations in patients with AS in a 12-month longitudinal study.
Methods. A total of 294 participants with AS meeting modified New York criteria completed clinical and psychological assessments at 6-month intervals. Psychological measures evaluated helplessness, depression and internality. Path analysis evaluated the direct and indirect effects of baseline disease activity on 12-month functional limitations via the psychological measures of helplessness, internality and depression at 6 months.
Results. Baseline disease activity demonstrated direct and indirect effects on 12-month functional limitations. Helplessness and depression, but not internality, served as mediators of the relationship between disease activity and functional limitations.
Conclusion. Higher baseline disease activity predicted greater functional limitations at 12 months through helplessness and depression. Our findings suggest that helplessness and depression may constitute future treatment targets in reducing functional limitations in patients with AS.
Ankylosing spondylitis; Disease activity; Functional limitations; Depression; Internality; Helplessness
Transforming growth factor-beta (TGF-b) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis- interstitial lung disease (SSc-ILD) and imatinib is a potent inhibitor of TGF-b and PDGF production. We report a phase I/IIa open-label pilot study of imatinib in patients with SSc-ILD. Our primary aim was to assess imatinib’s safety; we also explored efficacy.
We recruited 20 SSc patients with FVC< 85% predicted, dyspnea on exertion, and presence of ground glass appearance on HRCT. Patients received oral imatinib therapy (up to 600 mg/day) for a period of 1 year. Adverse events, pulmonary function tests, and modified Rodnan skin score (MRSS) were captured every 3 months. The course of lung function, HAQ-DI and MRSS were modeled over the length of study to explore efficacy.
The majority of patients were female (65%), Caucasian (75%) and had diffuse SSc (70%). The baseline mean (SD) FVC%predicted was 65.2 (14.0) and MRSS was 18.7 (10.1). Mean(SD) imatinib dose was 445 (125) mg/day. Of 20 patients, 12 completed the study, 7 discontinued due to adverse events (AEs), and 1 patient was lost to follow-up. Common AEs (≥ 20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new onset proteinuria. Treatment with imatinib showed a trend towards an improvement of FVC%predicted of 1.74% (p>0.05) and MRSS of 3.9 units (p< 0.001).
Use of high-dose daily (600 mg/day) imatinib in SSc-ILD was associated with a large number of AEs. Our AE experience suggests that doses lower than 600 mg/day imatinib may be appropriate and that further dose ranging is needed to understand the therapeutic index of imatinib in SSc.
imatinib; clinical trial; systemic sclerosis; scleroderma-related lung fibrosis
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.
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.
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.
Unlike in rheumatoid arthritis, smoking does not confer a risk for development of SSc, though it may impact disease severity.
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.
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.
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).
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.
Scleroderma; GENISOS; anti-U3-RNP; digital ulcer; HLA DRB1; and Scleroderma Family Registry
To determine the prevalence, correlates, and predictors of work disability (WD) in the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS). We hypothesized that WD in systemic sclerosis (SSc) is a function of demographic, clinical, and psychosocial factors.
Patients enrolled in the GENISOS cohort were subdivided in 3 groups: work disabled, working, and retired or homemakers. The latter group (n=29) was excluded from further analysis. We used logistic regression analysis with a forward hierarchical variable selection strategy to investigate the independent correlates of WD at enrollment. Cox regression proportional Hazard’s model with a similar variable selection strategy was utilized to determine the predictors of WD in those working at enrollment.
Overall, 284 patients with mean age of 48.7 years and disease duration of 2.5 (±1.6) years were enrolled into the GENISOS cohort, consisting of 83.5% female, 46.8% Caucasian, 28.9% Hispanic, and 20.4% African American. Patients were longitudinally followed for 3.9 (±3.6) years in 1438 study visits. At enrollment, 124 patients (43.7%) were work disabled whereas 131 (46.1%) were working. Lower education (p<0.001), higher Medsger Lung Severity Index (p=0.012), higher Fatigue Severity Score (FSS) (p=0.008), and less social support (p<0.001) correlated independently with WD. Of those working at baseline, 35 (26.7%) eventually developed WD. Non-Caucasian ethnicity (p=0.038), lower DLCO %predicted value (p=0.038), and higher FSS (p=0.009) at enrollment independently predicted WD on follow-up visits.
Demographic, clinical, and psychosocial factors correlate with WD cross-sectionally and predict WD longitudinally in the patients with SSc.
Work disability; Systemic Sclerosis; Medsger Lung Severity Index; ISEL; SF-36; Fatigue
To examine the predictive role of HLA genetic markers for scleroderma renal crisis (SRC) beyond the known clinical correlates in a large population of patients with systemic sclerosis (SSc).
SSc patients from the Scleroderma Family Registry and DNA Repository, Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) and rheumatology divisional registry at the University of Texas Health Science Center at Houston were included in the study. Relevant clinical data were obtained by chart review and autoantibodies were detected utilizing commercially available kits. HLA Class II genotyping was performed on extracted and purified genomic DNA.
Overall, 1519 SSc patients were included in this study, from which 90 patients (6%) had developed SRC. Among the 90 patients with SRC, diffuse cutaneous subtypes were found in 76%, anti-toposiomerase (ATA) in 9%, anti-centromere antibodies(ACA) in 2%, and anti-RNA polymerase III (ARA) in 50% of patients. In the multivariate analysis of clinical and demographic parameters, diffuse disease type and ARA were strong risk factors for presence of SRC, whereas ACA and ATA were protective. In the final multivariate analysis after inclusion of HLA alleles, we identified HLA-DRB1*0407 (OR=3.21, 95% CI 1.27–8.08; P=0.013) and DRB1*1304 (OR=4.51, 95% CI 1.30–15.65; P=0.018) as independent risk factors for SRC. Only 3 clinical characteristics, diffuse disease type, ARA, and ACA remained significant in the final model.
This study suggests that DRB1*0407 and *1304 are independent risk factors for development of SRC beyond the known clinical correlates.
To identify differentially expressed genes in peripheral blood cells
(PBC) of patients with ankylosing spondylitis (AS) relative to healthy
controls and controls with systemic inflammation.
We investigated PBC samples of 16 patients with AS and 14 matched
controls, in addition to systemic lupus erythematosus (SLE) and systemic
sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using
quantitative PCR. Subsequently, these genes were also validated in a
separate sample of 27 patients with AS [before and after antitumor necrosis
factor (anti-TNF) treatment] and 27 matched controls.
We identified 83 differentially expressed transcripts between AS
patients and controls. This gene list was filtered through the lists of
differentially expressed transcripts in SLE and SSc, which resulted in
identification of 52 uniquely dysregulated transcripts in AS. Many of the
differentially expressed genes belonged to Toll-like receptor (TLR) and
related pathways. TLR4 and TLR5 were the
only dysregulated TLR subtypes among AS patients. We confirmed the
overexpression of TLR4 and TLR5 in AS
patients in comparison to controls (p = 0.012 and p = 0.006, respectively)
and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample.
Similarly, TLR4 (p = 0.007) and TLR5 (p =
0.012) were significantly upregulated among the AS patients before anti-TNF
treatment in the confirmatory sample. TLR4 (p = 0.002) and
TLR5 (p = 0.025) decreased significantly after anti-TNF
PBC gene expression profiling in AS shows an upregulation of
TLR4 and TLR5. This supports the
importance of TLR subtypes in the pathogenesis of AS that are responsible
for the immune response to Gram-negative bacteria.
ANKYLOSING SPONDYLITIS; TOLL-LIKE RECEPTORS; IMMUNE SYSTEM; AUTOIMMUNITY; BACTERIA; GENE EXPRESSION PROFILING
Longitudinal studies examining the baseline predictors of fatigue in SSc have not been reported. Our objectives were to examine the course of fatigue severity over time and to identify baseline clinical, demographic, and psychosocial predictors of sequentially obtained fatigue scores in early SSc. We also examined baseline predictors of change in fatigue severity over time.
We analyzed 1090 longitudinal Fatigue Severity Scale (FSS) scores belonging to 256 patients who were enrolled in the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS). Predictive significance of baseline variables for sequentially obtained FSS scores was examined with generalized linear mixed models. Predictors of change in FSS over time were examined by adding an interaction term between the baseline variable and time-in-study to the model.
The patients' mean age was 48.6 years, 47% were Caucasians, and 59% had diffuse cutaneous involvement. The mean disease duration at enrollment was 2.5 years. The FSS was obtained at enrollment and follow-up visits (mean follow-up time = 3.8 years). Average baseline FSS score was 4.7(±0.96). The FSS was relatively stable and did not show a consistent trend for change over time (p = 0.221). In a multivariable model of objective clinical variables, higher Medsger Gastrointestinal (p = 0.006) and Joint (p = 0.024) Severity Indices, and anti-U1-RNP antibodies (p = 0.024) were independent predictors of higher FSS. In the final model, ineffective coping skills captured by higher Illness Behavior Questionnaire scores (p<0.001), higher self-reported pain (p = 0.006), and higher Medsger Gastrointestinal Severity Index (p = 0.009) at enrollment were independent predictors of higher longitudinal FSS scores. Baseline DLco % predicted was the only independent variable that significantly predicted a change in FSS scores over time (p = 0.013), with lower DLco levels predicting an increase in FSS over time.
This study identified potentially modifiable clinical and psychological factors that predict longitudinal fatigue severity in early SSc.
Sumoylation is involved in nucleolus-nucleoplasm transport of DNA topoisomerase I (topo I), which may associate with changes of cellular and topo I functions. Skin fibroblasts of patients with systemic sclerosis (SSc) exhibit profibrotic cellular changes. The aims of this study were to examine the catalytic function and sumoylation of topo I in the nuclei of SSc fibroblasts, a major cell type involved in the fibrotic process.
Eleven pairs of fibroblast strains obtained from nonlesional skin biopsies of SSc patients and age/sex/ethnicity-matched normal controls were examined for catalytic function of nuclear topo I. Immunoprecipitation (IP)-Western blots were used to examine sumoylation of fibroblast topo I. Real-time quantitative RT-PCR was used to measure transcript levels of SUMO1 and COL1A2 in the fibroblasts.
Topo I in nuclear extracts of SSc fibroblasts generally showed a significantly lower efficiency than that of normal fibroblasts in relaxing equivalent amounts of supercoiled DNA. Increased sumoylation of topo I was clearly observed in 7 of 11 SSc fibroblast strains. Inhibition of SUMO1 with SUMO1 siRNA improved the catalytic efficiency of topo I in the SSc fibroblasts. In contrast, sumoylation of recombinant topo I proteins reduced their catalytic function.
The catalytic function of topo I was decreased in SSc fibroblasts, to which increased sumoylation of topo I may contribute.