Aberrant long-chain fatty acid metabolism associated with evolving systemic sclerosis-associated pulmonary arterial hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n = 22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared with metabolites assayed in matched SSc patients who did not develop PAH (n = 22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 yr) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to 2 yr before clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including before clinical diagnosis and in mild disease.NEW & NOTEWORTHY Abnormal lipid metabolism is evident across time in the development of SSc-PAH, and dysregulated long-chain fatty acid metabolism predicts overt PAH.

Factors associated with physical function among people with systemic sclerosis: a SPIN cohort cross-sectional study.

OBJECTIVES: To compare physical function in systemic sclerosis (SSc, scleroderma) to general population normative data and identify associated factors. METHODS: Scleroderma Patient-centered Intervention Network Cohort participants completed the Physical Function domain of the Patient-Reported Outcomes Measurement Information System Version 2 upon enrolment. Multivariable linear regression was used to assess associations of sociodemographic, lifestyle, and disease-related variables. RESULTS: Among 2,385 participants, mean physical function T-score (43.7, SD = 8.9) was ∼2/3 of a standard deviation (SD) below the US general population (mean = 50, SD = 10). Factors associated in multivariable analysis included older age (-0.74 points per SD years, 95% CI -0.78 to -1.08), female sex (-1.35, -2.37 to -0.34), fewer years of education (-0.41 points per SD in years, -0.75 to -0.07), being single, divorced, or widowed (-0.76, -1.48 to -0.03), smoking (-3.14, -4.42 to -1.85), alcohol consumption (0.79 points per SD drinks per week, 0.45-1.14), BMI (-1.41 points per SD, -1.75 to -1.07), diffuse subtype (-1.43, -2.23 to -0.62), gastrointestinal involvement (-2.58, -3.53 to -1.62), digital ulcers (-1.96, -2.94 to -0.98), moderate (-1.94, -2.94 to -0.93) and severe (-1.76, -3.24 to -0.28) small joint contractures, moderate (-2.10, -3.44 to -0.76) and severe (-2.54, -4.64 to -0.44) large joint contractures, interstitial lung disease (-1.52, -2.27 to -0.77), pulmonary arterial hypertension (-3.72, -4.91 to -2.52), rheumatoid arthritis (-2.10, -3.64 to -0.56) and idiopathic inflammatory myositis (-2.10, -3.63 to -0.56). CONCLUSION: Physical function is impaired for many individuals with SSc and associated with multiple disease factors.

Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension.

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Cumulative disease damage and anti-PM/Scl antibodies are associated with a heavy burden of calcinosis in systemic sclerosis.

OBJECTIVES: Ectopic calcification (calcinosis) is a common complication of SSc, but a subset of SSc patients has a heavy burden of calcinosis. We examined whether there are unique risk factors for a heavy burden of calcinosis, as compared with a light burden or no calcinosis. METHODS: We reviewed the medical records of all patients in the Johns Hopkins Scleroderma Center Research Registry with calcinosis to quantify calcinosis burden using pre-specified definitions. We performed latent class analysis to identify SSc phenotypic classes. We used multinomial logistic regression to determine whether latent phenotypic classes and autoantibodies were independent risk factors for calcinosis burden. RESULTS: Of all patients, 29.4% (997/3388) had calcinosis, and 13.5% (130/963) of those with calcinosis had a heavy burden. The latent phenotypic class with predominantly diffuse skin disease and higher disease severity (characterized by pulmonary hypertension, interstitial lung disease, cardiomyopathy, severe RP, gastrointestinal involvement, renal crisis, myopathy and/or tendon friction rubs) was associated with an increased risk of both a heavy burden [odds ratio (OR) 6.92, 95% CI 3.66, 13.08; P < 0.001] and a light burden (OR 2.88, 95% CI 2.11, 3.95; P < 0.001) of calcinosis compared with the phenotypic class with predominantly limited skin disease. Autoantibodies to PM/Scl were strongly associated with a heavy burden of calcinosis (OR 17.31, 95% CI 7.72, 38.81; P < 0.001) and to a lesser degree a light burden of calcinosis (OR 3.59, 95% CI 1.84, 7.00; P < 0.001). CONCLUSIONS: Calcinosis burden is associated with cumulative SSc-related tissue damage. Independent of disease severity, autoantibodies to PM/Scl are also associated with a heavy burden of calcinosis.

Construct validity and reliability of the assessment of systemic sclerosis-associated raynaud's phenomenon (ASRAP) questionnaire.

OBJECTIVES: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: An international multicentre study validation study of the 27-item Assessment of Systemic sclerosis-associated RAynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1-week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning. RESULTS: Four hundred and twenty SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, p< 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, p< 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, p< 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (p< 0.05 for all comparisons). There was excellent repeatability at 1-week amongst patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, p< 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77 respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53-7.81, p= 0.029) was estimated. CONCLUSION: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP.

CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

OBJECTIVES: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures. METHODS: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables. RESULTS: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020). CONCLUSIONS: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

Gastroparesis in systemic sclerosis: a detailed analysis using whole-gut scintigraphy.

OBJECTIVES: Gastroparesis is a common complication of SSc. We sought to determine the degree of overlap between gastroparesis and dysmotility in other areas of the gut, correlate our findings with gastrointestinal (GI) symptoms, and examine associations between gastroparesis and SSc features. METHODS: Whole-gut scintigraphy was performed on SSc patients who were enrolled in the Johns Hopkins Scleroderma Cohort, for whom detailed longitudinal clinical and serologic data are collected. A subset of patients completed the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA GIT 2.0) to quantify their GI symptoms. We examined associations between the presence and severity of gastroparesis, GI symptoms, and SSc clinical features. RESULTS: Ninety-seven SSc patients with and without GI symptoms underwent whole-gut scintigraphy and completed the gastric emptying study. Of the 97, 34 (35%) met criteria for gastroparesis. Of the measures assessed, delayed liquid emptying captured more patients with delayed gastric transit than delayed solid emptying (74% vs 55%), and percentage liquid emptying correlated best with GIT Reflux (ρ = -0.33, P = 0.01) and Distension (ρ = -0.30, P = 0.03) scores. Of 33 patients with gastroparesis, 30 (91%) had abnormal transit in other areas of the GI tract. Higher anti-centromere protein B (CENP-B) titres correlated with slower gastric emptying (ρ = -0.26, P = 0.03), but no specific clinical features of SSc were associated with gastroparesis. CONCLUSIONS: Gastric emptying of liquids when given alongside solids may be more sensitive and provide a more clinically relevant measure of gastroparesis in SSc than solid gastric emptying or liquid gastric emptying alone. SSc patients with gastroparesis frequently have dysmotility in other areas of the GI tract, underscoring the need for whole-gut scintigraphy to evaluate the entire gut.

Troponin elevation independently associates with mortality in systemic sclerosis.

OBJECTIVES: Cardiac involvement is common in systemic sclerosis (SSc), and elevated troponin may be the only sign of ongoing myocardial disease. The objective was to determine whether the presence of elevated troponin associates with unique SSc characteristics and poor outcomes. METHODS: This retrospective, cross-sectional study included patients in the Johns Hopkins Scleroderma Center Research Registry with any troponin measurement in the past 10 years. Clinical data were compared between those with elevated versus normal troponin. Survival analyses including Cox proportional hazards and regression analyses were performed. RESULTS: 272 patients with a troponin measurement were identified. 83 (31%) had elevated troponin. Compared to those with a normal troponin level, those with elevated troponin level were more likely to have the diffuse SSc subtype (p=0.005), lower left ventricular ejection fraction (57.7 ± 20% vs. 64.4 ± 17.4%, p=0.007), lower forced vital capacity percent predicted (61.1 ± 18.8% vs. 66.8 ± 20.4%, p=0.03), higher right ventricular systolic pressure (51.4 ± 20.9 vs. 43.4 ± 15.9 mmHg, p=0.001), higher Medsger muscle and heart severity scores (p≤0.001), and higher frequency of mortality (28% vs. 9.5%, p≤0.0001). Patients with elevated troponin also have a 2.16-fold (95% CI 1.01-4.63, p=0.046) increased risk of death compared to those without elevated troponin even after adjusting for age, sex, disease duration, and cardiopulmonary risk factors. CONCLUSIONS: Troponin may be a useful prognostic biomarker that may identify a subset of patients with heart disease that may warrant closer clinical investigation.

Predicting clinical events using Bayesian multivariate linear mixed models with application to scleroderma.

BACKGROUND: Scleroderma is a serious chronic autoimmune disease in which a patient's disease state manifests in several irregularly spaced longitudinal measures of lung, heart, skin, and other organ systems. Threshold crossings of pulmonary and cardiac measures indicate potentially life-threatening key clinical events including interstitial lung disease (ILD), cardiomyopathy, and pulmonary hypertension (PH). The statistical challenge is to accurately and precisely predict these events by using all of the clinical history for the patient at hand and for a reference population of patients. METHODS: We use a Bayesian mixed model approach to simultaneously characterize each individual's future trajectories for several biomarkers. We estimate this model using a large population of patients from the Johns Hopkins Scleroderma Center Research Registry. The joint probabilities of critical lung and heart events are then calculated as a byproduct of the mixed model. RESULTS: The performance of this approach is substantially better than standard, more common alternatives. In order to predict an individual's risks in a clinical setting, we also develop a cross-validated, sequential prediction (CVSP) algorithm. As additional data are observed during a patient's visit, the algorithm sequentially produces updated predictions for the future longitudinal trajectories and for ILD, cardiomyopathy, and PH. The updated prediction distributions with little additional computing, for example within an electronic health record (EHR). CONCLUSIONS: This method that generates real-time personalized risk estimates has been implemented within the electronic health record system for clinical testing. To our knowledge, this work represents the first approach to compute personalized risk estimates for multiple scleroderma complications.

Gastrointestinal involvement in systemic sclerosis: diagnosis and management.

PURPOSE OF REVIEW: This review provides important updates in systemic sclerosis (SSc)-related gastrointestinal disease, with a particular focus on the diagnosis and management of dysmotility. RECENT FINDINGS: In the past 2 years, several studies were published that present interesting diagnostic insights into SSc and gastrointestinal dysmotility. Studies focusing on new therapies and the novel application of existing therapies, both in SSc and non-SSc-associated gastrointestinal dysmotility syndromes, demonstrate progress in the management of these challenging complications. SUMMARY: SSc gastrointestinal disease is heterogeneous in its clinical presentation, which presents a challenge in diagnosis and management. Objective studies may help to identify patterns of gastrointestinal dysmotility and more specifically target therapy. A variety of drugs are now available or are under study in the management of gastrointestinal dysmotility, such as prucalopride, intravenous immunoglobulin, pyridostigmine, linaclotide, relamorelin, and others. These drugs may improve symptoms and quality of life in SSc gastrointestinal patients. Combination therapies are also under study. Electroacupuncture, dietary intervention (e.g. medical nutrition therapy, low FODmap diet), and medical cannibus may also play a role in alleviating patient symptoms; however, more data are needed to define the role of these interventions in SSc.

Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer.

OBJECTIVES: Recent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma. Investigating cancer risk in these biologically relevant subsets may provide an opportunity to develop personalised cancer screening guidelines. In this study, we examined cancer risk in distinct serologic and phenotypic scleroderma subsets and compared estimates with the general population. METHODS: Patients in the Johns Hopkins Scleroderma Center observational cohort were studied. Overall and site-specific cancer incidence was calculated in distinct autoantibody and scleroderma phenotypic subsets, and compared with the Surveillance, Epidemiology and End Results registry, a representative sample of the US population. RESULTS: 2383 patients with scleroderma contributing 37 686 person-years were studied. 205 patients (8.6%) had a diagnosis of cancer. Within 3 years of scleroderma onset, cancer risk was increased in patients with RNA polymerase III autoantibodies (antipol; standardised incidence ratio (SIR) 2.84, 95% CI 1.89 to 4.10) and those lacking centromere, topoisomerase-1 and pol antibodies (SIR 1.83, 95% CI 1.10 to 2.86). Among antipol-positive patients, cancer-specific risk may vary by scleroderma subtype; those with diffuse scleroderma had an increased breast cancer risk, whereas those with limited scleroderma had high lung cancer risk. In contrast, patients with anticentromere antibodies had a lower risk of cancer during follow-up (SIR 0.59, 95% CI 0.44 to 0.76). CONCLUSIONS: Autoantibody specificity and disease subtype are biologically meaningful filters that may inform cancer risk stratification in patients with scleroderma. Future research testing the value of targeted cancer screening strategies in patients with scleroderma is needed.

ANCA-associated vasculitis in scleroderma: A renal perspective
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AIMS: Overlap syndrome of ANCA-associated vasculitis (AAV) and scleroderma (SSc) is rare with conflicting data on renal outcomes. We describe the clinical characteristics and treatment outcome of ANCA-associated glomerulonephritis (AAG) in SSc patients followed at a single center. MATERIALS AND METHODS: We conducted a retrospective study of 3,570 patients in our SSc database to identify SSc patients who subsequently developed AAV with renal involvement. Patient demographics, serology, renal function, renal histology, and treatment outcomes were assessed. RESULTS: Of the 3,570 patients, we identified 7 patients who developed acute glomerulonephritis, and all were ANCA positive. The mean age at SSc diagnosis was 47 years, 4 patients were female, and 6 had diffuse SSc. Anti-nuclear antibody (ANA) was positive in all. Mean time of onset of AAV from time of diagnosis of SSc was 6 years, and all were myeloperoxidase (MPO) positive. Patients presented with hematuria, proteinuria, with or without rise in serum creatinine, and all patients had biopsy-proven crescentic glomerulonephritis. One patient required dialysis at presentation. Five patients were treated with cyclophosphamide and steroids, and 2 were treated with rituximab and steroids. Of the 7 patients, 4 did not receive maintenance immunosuppression. Three patients died, and 1 of them experienced relapse with fulminant alveolar hemorrhage. CONCLUSION: AAG in SSc is rare, with disease manifestation and course similar to that of AAV. This case series demonstrates that disease remission can be achieved with standard induction therapy. Vasculitis relapse can occur, and similar to idiopathic AAV, maintenance immunosuppression should be initiated to maintain remission.
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Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. METHODS AND RESULTS: RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. CONCLUSIONS: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Evaluation of cancer-associated myositis and scleroderma autoantibodies in breast cancer patients without rheumatic disease.

OBJECTIVES: Systemic sclerosis (scleroderma) and dermatomyositis are two prototypic autoimmune diseases that are strongly associated with malignancy. While specific autoantibodies in these diseases are markers of an increased risk of cancer at scleroderma and dermatomyositis onset, it is not known whether these autoantibodies are biomarkers of cancer risk in patients without rheumatic disease. METHODS: In a matched case-control study of women without rheumatic disease, identified from a familial breast cancer cohort, 50 breast cancer cases and 50 controls were assayed for 3 autoantibodies that are known markers of cancer-associated scleroderma and dermatomyositis: anti-RNA polymerase III, anti-NXP2, and anti-TIF1γ. RESULTS: No subject had moderate or strong autoantibody positivity. Eleven women were borderline positive for at least one autoantibody. The prevalence of borderline autoantibody positivity did not differ between cases and controls. CONCLUSIONS: Our results suggest that scleroderma and dermatomyositis autoantibodies are cancer biomarkers only in patients with clinical manifestations of specific rheumatic diseases and are unlikely to improve risk stratification for cancer in the general population. However, prospective studies are needed to examine whether scleroderma and dermatomyositis autoantibodies are markers of malignancy in other cancer types.

Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry.

OBJECTIVES: To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc). METHODS: PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP≥64 and NT-proBNP≥210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP≥180, NT-proBNP≥553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients. RESULTS: 172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP≥64 pg/mL was 71% and 59%; and for NT-proBNP≥210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ≥1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001). CONCLUSIONS: NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.

Biomarkers in Scleroderma: Progressing from Association to Clinical Utility.

Scleroderma is a heterogenous disease characterized by autoimmunity, a characteristic vasculopathy, and often widely varying extents of deep organ fibrosis. Recent advances in the understanding of scleroderma's evolution have improved the ability to identify subgroups of patients with similar prognosis in order to improve risk stratification, enrich clinical trials for patients likely to benefit from specific therapies, and identify promising therapeutic targets for intervention. High-throughput technologies have recently identified fibrotic and inflammatory effectors in scleroderma that exhibit strong prognostic ability and may be tied to disease evolution. Increasingly, the use of collections of assayed circulating proteins and patterns of gene expression in tissue has replaced single-marker investigations in understanding the evolution of scleroderma and in objectively characterizing disease extent. Lastly, identification of shared patterns of disease evolution has allowed classification of patients into latent disease subtypes, which may allow rapid clinical prognostication and targeted management in both clinical and research settings. The concept of biomarkers in scleroderma is expanding to include nontraditional measures of aggregate protein signatures and disease evolution. This review examines the recent advances in biomarkers with a focus on those approaches poised to guide prospective management or themselves serve as quantitative surrogate disease outcomes.

Scleromyxedema.

PURPOSE OF REVIEW: To synthesize the current known data on pathogenesis and treatment of scleromyxedema. This review will also highlight the clinical presentation, systemic features and outcomes and distinguishing features between scleromyxedema and scleroderma, as a common mimic. RECENT FINDINGS: Most recent publications have focused on describing treatment responses with novel therapies, with the majority of cases reporting success with intravenous immunoglobulin. However, other therapies suggest promise as well in case reports, including bortezomib, thalidomide and stem cell transplantation. There is little information on pathogenesis; however, focus has been on the relationship between the mucin deposition and the monoclonal immunoglobulins that are seen in almost all patients with scleromyxedema. SUMMARY: Scleromyxedema is a rare mucinous deposition disorder that shares clinical features with scleroderma but has important distinguishing features in clinical presentation and major organ complications that should be recognized. Patients typically respond well to therapy as highlighted in several larger series, but poor outcomes are reported in a few cases.

International consensus criteria for the diagnosis of Raynaud's phenomenon.

Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud's phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud's-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as "uncertain" for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists "agreed" were "appropriate" diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were "appropriate", 12 items had "uncertain" appropriateness, and 13 items were "inappropriate" to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were "appropriate and accurate" for use by physicians to diagnose patients with RP.