False Positive Anti-Topoisomerase I (Scl-70) Antibody Results in Clinical Practice: A Case Series From a Scleroderma Referral Center

PURPOSE: To determine if some patients who tested positive for anti-Scl-70 antibody in clinical practice, but did not have classifiable systemic sclerosis, were negative for anti-Scl-70 antibody by the more specific immunodiffusion method of testing. METHODS: Patients evaluated by a rheumatologist at a Scleroderma referral center who had tested positive for anti-Scl-70 antibody prior to referral, but did not have classifiable SSc based on clinical criteria, were invited to undergo testing for anti-Scl-70 antibody by immunodiffusion. Patient demographics and clinical features were recorded at the time of their evaluation, and diagnostic testing results were reviewed using the medical records. RESULTS: 52 patients were enrolled over an 8-year period, with 48 (92.3%) testing negative and 4 (7.7%) testing positive for anti-Scl-70 antibody by immunodiffusion. Of the 48 patients who tested negative, 18 (37.5%) tested negative for ANA by indirect immunofluorescence, 33 (68.8%) did not have Raynaud\u27s phenomenon, and 43 (89.6%) had ≤1 clinical criteria items based on the 2013 ACR/EULAR SSc classification criteria. Nevertheless, 21 (43.8%) patients who were negative for anti-Scl-70 antibody by immunodiffusion had undergone a chest CT and 14 (29.2%) had undergone an echocardiogram. A total of 23 patients had at least one follow up clinic visit. 3 out of 4 patients who were positive for anti-Scl-70 antibody by immunodiffusion, but none of the 19 patients who tested negative by immunodiffusion, developed sufficient criteria during follow up to be classified as SSc. CONCLUSION: Assays for anti-Scl-70 antibody in commercial laboratories that are commonly utilized in clinical practice can produce false positive results. These results can lead to angst for patients, as well as unnecessary referrals and diagnostic evaluations

Blood Neutrophil Count and Neutrophil-to-Lymphocyte Ratio for Prediction of Disease Progression and Mortality in Two Independent Systemic Sclerosis Cohorts

OBJECTIVE: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc). METHODS: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity. Longitudinal analyses were performed using generalized linear mixed models. Cox proportional hazards models evaluated the predictive significance of these cell counts for mortality. RESULTS: Of the 447 SSc patients in the GENISOS cohort at the time of analysis, 377 (84.3%) had available baseline blood neutrophil and lymphocyte counts. Higher baseline neutrophil count and NLR predicted lower serially obtained FVC% (b = -4.74, P = 0.009 and b = -2.68, P = 0.028, respectively) and higher serially obtained MRSS (b = 4.07, P \u3c 0.001 and b = 2.32, P \u3c 0.001, respectively). Longitudinal neutrophil and NLR measurements also significantly correlated with lower concurrently obtained FVC% measurements and higher concurrently obtained MRSS. Baseline neutrophil count and NLR predicted increased risk of long-term mortality, even after adjustment for baseline demographic and clinical factors (hazard ratio [HR] 1.42, P = 0.02 and HR 1.48, P \u3c 0.001, respectively). The predictive significance of higher baseline neutrophil count and NLR for declining FVC% and increased long-term mortality was confirmed in the SLS II. CONCLUSION: Higher blood neutrophil count and NLR are predictive of more severe disease course and increased mortality, indicating that these easily obtainable laboratory studies might be a reflection of pathologic immune processes in SSc

Blood Neutrophil Count and Neutrophil-to-Lymphocyte Ratio for Prediction of Disease Progression and Mortality in Two Independent Systemic Sclerosis Cohorts

OBJECTIVE: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc). METHODS: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity. Longitudinal analyses were performed using generalized linear mixed models. Cox proportional hazards models evaluated the predictive significance of these cell counts for mortality. RESULTS: Of the 447 SSc patients in the GENISOS cohort at the time of analysis, 377 (84.3%) had available baseline blood neutrophil and lymphocyte counts. Higher baseline neutrophil count and NLR predicted lower serially obtained FVC% (b = -4.74, P = 0.009 and b = -2.68, P = 0.028, respectively) and higher serially obtained MRSS (b = 4.07, P \u3c 0.001 and b = 2.32, P \u3c 0.001, respectively). Longitudinal neutrophil and NLR measurements also significantly correlated with lower concurrently obtained FVC% measurements and higher concurrently obtained MRSS. Baseline neutrophil count and NLR predicted increased risk of long-term mortality, even after adjustment for baseline demographic and clinical factors (hazard ratio [HR] 1.42, P = 0.02 and HR 1.48, P \u3c 0.001, respectively). The predictive significance of higher baseline neutrophil count and NLR for declining FVC% and increased long-term mortality was confirmed in the SLS II. CONCLUSION: Higher blood neutrophil count and NLR are predictive of more severe disease course and increased mortality, indicating that these easily obtainable laboratory studies might be a reflection of pathologic immune processes in SSc

Reactome pathway analysis from whole-blood transcriptome reveals unique characteristics of systemic sclerosis patients at the preclinical stage

ObjectiveThis study aims to characterize differential expressed pathways (DEP) in subjects with preclinical systemic sclerosis (PreSSc) characterized uniquely by Raynaud phenomenon, specific autoantibodies, and/or capillaroscopy positive for scleroderma pattern.MethodsWhole-blood samples from 33 PreSSc with clinical prospective data (baseline and after 4 years of follow-up) and 16 matched healthy controls (HC) were analyzed for global gene expression transcriptome analysis via RNA sequencing. Functional Analysis of Individual Microarray Expression method annotated Reactome individualized pathways. ANOVA analysis identified DEP whose predictive capability were tested in logistic regression models after extensive internal validation.ResultsAt 4 years, 42.4% subjects progressed (evolving PreSSc), while the others kept stable PreSSc clinical features (stable PreSSc). At baseline, out of 831 pathways, 541 DEP were significant at a false discovery rate <0.05, differentiating PreSSc versus HC with an AUROC = 0.792 ± 0.242 in regression models. Four clinical groups were identified via unsupervised clustering (HC, HC and PreSSc with HC-like features, PreSSc and HC with PreSSc-like features, and PreSSc). Biological signatures changed with disease progression while remaining unchanged in stable subjects. The magnitude of change was related to the baseline cluster, yet no DEP at baseline was predictive of progression. Disease progression was mostly related to changes in signal transduction pathways especially linked to calcium-related events and inositol 1,4,5-triphosphate metabolism.ConclusionPreSSc had distinguished Reactome pathway signatures compared to HC. Progression to definite SSc was characterized by a shift in biological fingertips. Calcium-related events promoting endothelial damage and vasculopathy may be relevant to disease progression

Searching for gravitational waves from known pulsars

We present upper limits on the amplitude of gravitational waves from 28 isolated pulsars using data from the second science run of LIGO. The results are also expressed as a constraint on the pulsars' equatorial ellipticities. We discuss a new way of presenting such ellipticity upper limits that takes account of the uncertainties of the pulsar moment of inertia. We also extend our previous method to search for known pulsars in binary systems, of which there are about 80 in the sensitive frequency range of LIGO and GEO 600.Comment: Accepted by CQG for the proceeding of GWDAW9, 7 pages, 2 figure

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Peripheral blood gene expression profiling shows predictive significance for response to mycophenolate in systemic sclerosis-related interstitial lung disease.

ObjectivesTo characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD).MethodsPBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of baseline composite modular scores for the course of forced vital capacity (FVC) per cent predicted measurements from 3 to 12 months.Results134 patients with SSc-ILD (CYC=69 and MMF=65) were investigated. CYC led to an upregulation of erythropoiesis, inflammation and myeloid lineage-related modules and a downregulation of lymphoid lineage-related modules. The modular changes resulting from MMF treatment were more modest and included a downregulation of plasmablast module. In the longitudinal analysis, none of the baseline transcript module scores showed predictive significance for FVC% course in the CYC arm. In contrast, in the MMF arm, higher baseline lymphoid lineage modules predicted better subsequent FVC% course, while higher baseline myeloid lineage and inflammation modules predicted worse subsequent FVC% course.ConclusionConsistent with the primary mechanism of action of MMF on lymphocytes, patients with SSc-ILD with higher baseline lymphoid module scores had better FVC% course, while those with higher myeloid cell lineage activation score had poorer FVC% course on MMF