IRF5 polymorphism predicts prognosis in patients with systemic sclerosis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis.

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.

Primary cardiac angiosarcoma diagnosed in the first trimester of pregnancy.

Primary cardiac angiosarcoma (PCAS) is a malignancy seldom seen in pregnancy. A 23-year-old G1P0 Chinese female was found to have PCAS during her first trimester when she presented with tamponade physiology. The transthoracic echocardiography (TTE) results did not indicate the presence of an intracardiac lesion, and pericardial fluid cytology analysis showed no evidence of malignancy. Cardiac magnetic resonance imaging (CMRI) exhibited a right atrial mass, and tissue biopsy indicated a high-grade angiosarcoma. MRI of the abdomen was suggestive of liver metastasis. She underwent an abortion and was started on combination chemotherapy, with a reduction in both the cardiac and liver masses. In cardiac angiosarcomas, advanced imaging modalities such as MRI should be utilised when there is high clinical suspicion or in the case of pregnancy when trying to minimise foetal harm. Prognosis is poor, and a standardised treatment protocol regardless of pregnancy continues to elude the medical community.

Predicting Outcome in Idiopathic Pulmonary Fibrosis: Addition of Fibrotic Score at Thin-Section CT of the Chest to Gender, Age, and Physiology Score Improves the Prediction Model.

PURPOSE: To assess the impact of adding thin-section CT-derived semiquantitative fibrotic score to gender, age, and physiology (GAP) model for predicting survival in idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: In this retrospective study of 194 patients with IPF, primary outcome was transplant-free survival. Two thoracic radiologists visually estimated the percentage of reticulation and honeycombing at baseline thin-section CT, which were added to give fibrotic score. For analysis, fibrotic score cutoff (x) determined by using receiver operating characteristic analysis categorized patients into group A (3). Combining the above categories gave four groups (A1, A2, B1, B2). Kaplan-Meier survival analysis was performed with comparison statistics (log-rank test), and hazard ratios were calculated by using the Cox model. RESULTS: The study patients included 141 men (72.7%), with average age of 66.1 years ± 9.1 (standard deviation). Eighty-four patients (43.3%) has stage I disease with a median follow up of 3.3 years. The interobserver agreement for thin-section CT fibrotic score was substantial (83.3%; κ = 0.64). The optimal cutoff for fibrotic score was 25% (x), with area under the curve of 0.654 (95% confidence interval [CI]: 0.569, 0.74). Survival for group A1 was significantly better than in the other three groups (P < .001). The hazard ratios for respective groups were as follows: B1 was 4.03 (95% CI: 2.02, 8.07), A2 was 4.10 (95% CI: 1.89, 8.87), and B2 was 5.62 (95% CI: 2.86, 11.06) (P < .001 for all). Within the group with GAP score less than or equal to 3 (A1, B1), participants with higher fibrotic score (B1) had four times the increased risk of death or transplantation (P < .001). CONCLUSION: Incorporating semiquantitative fibrotic score from thin-section CT to GAP score provides an improved prediction model for survival in idiopathic pulmonary fibrosis.© RSNA, 2019See also the commentary by Chung in this issue.

Overview of idiopathic pulmonary fibrosis (IPF) and evidence-based guidelines.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of interstitial lung disease (ILD), characterized by fibrosis and worsening lung function, that primarily occurs in those 50 years and older. Various causes including genetic susceptibility, environmental risk factors, and exposures have been suggested in the literature. All of these cause repetitive micro-injury to the lung tissue and vasculature, which triggers a cascade of inflammatory response and fibrosis. Symptoms are nonspecific and most patients present several years after the initial radiographic changes occur. Diagnosis requires a high index of clinical suspicion supported by distinct radiographic and/or histopathologic findings. Median survival is estimated at between 2 and 3 years after diagnosis. Other than lung transplantation, no treatment has shown survival benefit. Two most recently approved medications for IPF, pirfenidone and nintedanib, can slow disease progression. Most patients have several comorbid conditions that can affect the course of their disease, including gastroesophageal reflux disease, obstructive sleep apnea, cardiomyopathy, and pulmonary hypertension. Observational studies suggested possible benefits in transplant-free survival and patients' outcomes with these medications. In addition to the new treatment options and optimal management of the comorbidities in patients with IPF, pulmonary rehabilitation remains a critical part of management and has been shown to improve quality of life and functional level. Considering the complexity of the diagnosis and management, the American Thoracic Society and European Respiratory Society published a joint statement on diagnosis and treatment of IPF. This article provides an overview of the epidemiology, pathophysiology, and guideline-recommended approaches for the diagnosis and management of IPF.

Predictors of early readmission among patients 40 to 64 years of age hospitalized for chronic obstructive pulmonary disease.

RATIONALE: Various causes can contribute to the high rates of readmission among patients hospitalized with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine the frequency and predictors of early readmission among patients aged 40-64 years, hospitalized with COPD. METHODS: In a retrospective cohort study, using a large national commercial insurance database, we obtained the clinical information within 12 months of the index hospitalization and 30 days after discharge. MEASUREMENTS AND MAIN RESULTS: Primary outcome was early readmission, defined as hospitalization within 30 days of discharge. We categorized predictor variables as patient, provider, and system factors, and compared these variables between patients readmitted and those not readmitted. Logistic regression was used for multivariable analysis. Of 8,263 patients who met the inclusion criteria, 741 (8.9%) had early readmission. Multivariable analysis showed patient factors (male, history of heart failure, lung cancer, osteoporosis, and depression), provider factors (no prior prescription of statin within 12 mo of the index hospitalization and no prescription of short-acting bronchodilator, oral steroid and antibiotic on discharge), and system factors (length of stay, <2 or >5 d and lack of follow-up visit after discharge) were associated with early readmission among patients hospitalized with COPD. The C-statistic of the model including patient characteristics was 0.677 (95% confidence interval, 0.656-0.697), which was improved to 0.717 (95% confidence interval, 0.702-0.732) after addition of provider- and system-based factors. CONCLUSIONS: One of 11 patients hospitalized with COPD is readmitted within 30 days of discharge. Provider and system factors are important modifiable risk factors of early readmission.

Guideline adherence in management of stable chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the only leading cause of death with rising morbidity and mortality. Clinical practice guidelines (CPGs) to optimize pharmacotherapy for patients with COPD have been updated based on promising results of randomized clinical trials. We examined the frequency of and factors associated with guideline adherence by physicians in clinical practice at an academic medical center. METHODS: Patients with a clinical diagnosis of COPD, confirmed by spirometry, who presented to the ambulatory clinics, were enrolled. The primary outcome was provider's adherence to the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Subjects were categorized as guideline-concordant who received a rescue inhaler (all patients), or at least one long-acting bronchodilator (stage II), or at least one long-acting bronchodilator plus an inhaled corticosteroid (stage III-IV). Demographics, clinical information and type of provider were recorded. Provider type was classified as primary care physician (PCP), pulmonologist, or co-management by both. RESULTS: Among 450 subjects who met study criteria, 246 (54.7%) received guideline-concordant treatment. Age, sex, race, disease severity, and co-morbidities were not associated with guideline adherence. Multivariate analysis showed that patients co-managed by a PCP and pulmonologist had a higher likelihood of receiving guideline-concordant treatment than those managed by one or the other (Odds Ratio: 4.59; 95% Confidence Interval: 2.92, 7.22, p < 0.001). CONCLUSIONS: Just over half of stable COPD patients receive guideline-concordant care. Co-management by a PCP and pulmonologist increases the likelihood of receiving guideline-concordant inhaler therapy.

Measuring illness behavior in patients with systemic sclerosis.

OBJECTIVE: Illness behaviors (cognitive, affective, and behavioral reactions) among individuals with systemic sclerosis (SSc; scleroderma) are of clinical concern due to relationships between these behaviors and physical and mental quality of life, such as pain and symptoms of depression. Self-report measures with good psychometric properties can aid in the accurate assessment of illness behavior. The Illness Behavior Questionnaire (IBQ) was designed to measure abnormal illness behaviors; however, despite its longstanding use, there is disagreement regarding its subscales. The goal of the present study was to evaluate the validity of the IBQ in a cohort of patients with SSc. METHODS: Patients with SSc (n = 278) completed the IBQ at enrollment into the Genetics Versus Environment in Scleroderma Outcome Study. Structural validity of previously derived factor solutions was investigated using confirmatory factor analysis. Exploratory factor analysis was utilized to derive SSc-specific subscales. RESULTS: None of the previously derived structural models were supported for SSc patients. Exploratory factor analysis supported an SSc-specific factor structure with 5 subscales. Validity analyses suggested that the subscales were generally independent of disease severity, but were correlated with other health outcomes (i.e., fatigue, pain, disability, social support, and mental health). CONCLUSION: The proposed subscales are recommended for use in SSc, and can be utilized to capture illness behavior that may be of clinical concern.

Right bundle branch block: a predictor of mortality in early systemic sclerosis.

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

Gastric antral vascular ectasia and its clinical correlates in patients with early diffuse systemic sclerosis in the SCOT trial.

OBJECTIVE: To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; "watermelon stomach") in early diffuse systemic sclerosis (SSc). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Long-Term Survival, Toxicity Profile, and role of F-18 FDG PET/CT scan in Patients with Progressive Neuroendocrine Tumors Following Peptide Receptor Radionuclide Therapy with High Activity In-111 Pentetreotide.

AIM: To study the long term benefits, toxicity and survival rate in patients with neuroendocrine tumors receiving multiple cycles of high activity In-111 Pentetreotide therapy. Moreover, our secondary aim was to evaluate the value of F-18 FDG PET-CT scan as prognostic indicator in this group of patients. BACKGROUND: Neuroendocrine tumors are a heterogeneous group of malignancies which are usually metastatic at diagnosis. Standard chemotherapy in these patients is associated with appreciable adverse events and low effectiveness. Since 1990s, Peptide receptor radionuclide therapy (PRRT) with radio-labeled somatostatin analogues has been introduced as a new method of treatment in patients with unresectable and/or metastatic neuroendocrine tumors expressing high levels of Somatostatin receptors. METHODS: 112 patients with progressive disseminated and unresectable neuroendocrine tumor (stage III and stage IV) were enrolled in a non-randomized trial in an out-patient setting. High activity In-111 Pentetreotide (500 mCi (18.5 GBq) per cycle) was administered as an intravenous infusion over 3 hours and repeated therapy cycles every 9-12 weeks in eligible patients up to maximum of 4 cycles. Response to therapy was evaluated by clinical imaging using the RECIST criteria, metabolic criteria and patient's quality of life questionnaire. Dosimetry and biodistribution studies were also performed. Finally, Kaplan-Meier survival analysis was performed for patients followed for greater than 12 months. The relationship between pretreatment F-18 FDG PET-CT scan status and survival was determined by two-tailed Student's t-test in 42 patients who underwent pre-therapy PET scans. RESULTS: For an average of 25 (median 18.65) months following the therapy, patients were evaluated for any evidence of toxicity. No significant acute toxicity was observed in patients. Grade II or III hematological toxicity (7.6% of patients), liver toxicity (18.4%) and also grade I renal toxicity (6.1%) was observed in 92 evaluable patients. Radiological responses were evaluated for an average of 29 months following their last cycle of therapy and results were analyzed by the RECIST criteria. Majority (85%) of patients had stable disease (SD), partial response (PR) rate was 7.5% and progressive disease (PD) was observed in 7.5% of patients. The average survival was 24.67 months after 2 cycles of therapy, 30.53 months after 3 cycles of therapy and 30.19 months after 4 cycles of therapy. Of the 42 patients who had pretreatment PET-CT imaging, 31 patients had positive F-18 FDG scans (SUV > 2.5) with an average survival time of 18.9 months (range 1.4-45.8 months) and 11 patients had negative F-18 FDG scans (SUV ≤ 2.5) with an average survival time of 31.8 months (range 7.4-42.9 months). Survival times for FDG negative patients were significantly longer than those for FDG positive patients (p = 0.001 with 95% confidence). CONCLUSION: High activity In-111 therapy is a safe and effective therapy for patients with progressive disseminated neuroendocrine tumors. No major hematological, renal and hepatic toxicities were observed. There was an increase in survival time particularly in patients with lower degree of liver involvement as well as patients who received three or more cycles of therapy, as compared to historical data. Pre-treatment FDG status may be a predictor of survival following In-111 pentetreotide therapy.

Decreased catalytic function with altered sumoylation of DNA topoisomerase I in the nuclei of scleroderma fibroblasts.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The catalytic function of topo I was decreased in SSc fibroblasts, to which increased sumoylation of topo I may contribute.

Predictors of fatigue severity in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This study identified potentially modifiable clinical and psychological factors that predict longitudinal fatigue severity in early SSc.

Determinants of work disability in patients with systemic sclerosis: a longitudinal study of the GENISOS cohort.

OBJECTIVES: 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. METHODS: 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. RESULTS: Overall, 284 patients with a 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% white, 28.9% Hispanic, and 20.4% African American. Patients were longitudinally followed in 1438 study visits. At enrollment, 124 patients (43.7%) were work disabled, whereas 131 (46.1%) were working. Lower level of education (P < 0.001), higher Medsger Lung Severity Index (P = 0.012), higher Fatigue Severity Score (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-white ethnicity (P = 0.038), lower DLCO % predicted value (P = 0.038), and higher Fatigue Severity Score (P = 0.009) at enrollment independently predicted WD on follow-up visits. CONCLUSIONS: WD is a major problem among SSc patients and its prevalence is substantially higher than other rheumatic conditions. Demographic, clinical, and psychosocial factors correlate with WD cross-sectionally and predict WD longitudinally in these patients.

Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5.

OBJECTIVE: 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. METHODS: 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 anti-tumor necrosis factor (anti-TNF) treatment] and 27 matched controls. RESULTS: 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 treatment. CONCLUSION: 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.

Anti-fibrillarin antibody in African American patients with systemic sclerosis: immunogenetics, clinical features, and survival analysis.

OBJECTIVE: 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. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc. METHODS: Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival. RESULTS: Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger 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 to patients without AFA (p = 0.493). CONCLUSION: Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. 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. Presence of AFA did not change survival.

Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.

INTRODUCTION: The objective of the present study was to examine the association of baseline demographic and clinical characteristics with sequentially obtained measurements of forced vital capacity (FVC), expressed as a percentage of the predicted value, and to identify predictors of the decline rate in FVC over time in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS). METHODS: To date, 266 patients have been enrolled in GENISOS, a prospective, observational cohort of patients with early systemic sclerosis. In addition to pulmonary function tests (PFTs), clinical and laboratory data were obtained from each patient. We analyzed 926 FVC measurements utilizing generalized linear mixed models. The predictive significance of baseline variables for the decline rate in FVC was investigated by the interaction term between the variable and the follow-up time within the first 3 years after enrollment as well as throughout the entire follow-up time. RESULTS: The cohort consisted of 125 white, 54 African American, and 77 Hispanic patients with average disease duration of 2.5 years at enrollment. The mean follow-up time was 3.8 years, ranging up to 11.4 years. A number of baseline variables, including antibody status, African American ethnicity, disease type, baseline PFT values, modified Rodnan Skin Score, fibrosis on chest radiograph, and lung and skin subscores of the Severity Index, were associated with serially measured FVC levels. However, only the presence of anti-topoisomerase I antibodies (ATA) was associated with lower FVC levels (P < 0.001) as well as accelerated decline rate in FVC within the first 3 years of follow-up (P = 0.02). None of the baseline variables predicted the rate of decline in FVC on long-term follow-up. Patients with rapidly progressive ILD, however, were under-represented in the long-term follow-up group because the accelerated rate of decline in FVC was associated with poor survival (P = 0.001). CONCLUSIONS: Presence of ATA was the only baseline variable associated with differential FVC levels, predicting the rate of decline in FVC within the first 3 years of follow-up. The association of faster decline in FVC with poor survival further emphasizes the need for identification of predictive biomarkers by collection of genetic information and serial blood samples in cohort studies.