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1.  Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study 
Cutolo, Maurizio | Herrick, Ariane L. | Distler, Oliver | Becker, Mike O. | Beltran, Emma | Carpentier, Patrick | Ferri, Clodoveo | Inanç, Murat | Vlachoyiannopoulos, Panayiotis | Chadha‐Boreham, Harbajan | Cottreel, Emmanuelle | Pfister, Thomas | Rosenberg, Daniel | Torres, Juan V. | Smith, Vanessa | Cutolo, Maurizio | Herrick, Ariane L. | Distler, Oliver | Becker, Mike | Beltran, Emma | Carpentier, Patrick | Ferri, Clodoveo | Inanç, Murat | Vlachoyiannopoulos, Panayiotis | Smith, Vanessa | Erlacher, L | Hirschl, M | Kiener, HP | Pilger, E | Smith, V | Blockmans, D | Wautrecht, J‐C | Becvár, R | Carpentier, P | Frances, C | Lok, C | Sparsa, A | Hachulla, E | Quere, I | Allanore, Y | Agard, C | Riemekasten, G | Hunzelmann, N | Stücker, M | Ahmadi‐Simab, K | Sunderkötter, C | Wohlrab, J | Müller‐Ladner, U | Schneider, M | Vlachoyianopoulos, P | Vassilopoulos, D | Drosos, A | Antonopoulos, A | Balbir‐Gurman, A | Langevitz, P | Rosner, I | Levy, Y | Cutolo, M | Bombardieri, S | Ferraccioli, G | Mazzuca, S | Grassi, W | Lunardi, C | Airó, P | Riccieri, V | Voskuyl, AE | Schuerwegh, A | Santos, L | Rodrigues, AC | Grilo, A | Amaral, MC | Román Ivorra, JA | Castellvi, I | Distler, O | Spertini, F | Müller, R | Inanç, M | Oksel, F | Turkcapar, N | Herrick, A | Denton, C | McHugh, N | Chattopadhyay, C | Hall, F | Buch, M
To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6‐month period in patients with systemic sclerosis (SSc).
In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses.
Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow‐up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681–0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510–0.756).
This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs.
PMCID: PMC5129545  PMID: 27111549
2.  Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis 
Arthritis and rheumatism  2011;63(5):1396-1404.
Tissue fibrosis caused by pathological activation of fibroblasts with increased synthesis of extracellular matrix components is a major hallmark of systemic sclerosis (SSc). Notch signalling regulates tissue differentiation and pathologic activation of Notch signaling has been implicated in the pathogenesis of various malignancies. The aim of the present study was to investigate the role of Notch signaling in SSc and to evaluate the therapeutic potential of Notch inhibition for the treatment of fibrosis.
Activation of the Notch pathways was analyzed by staining for the Notch intracellular domain (NICD) and quantification of the mRNA levels hes-1. Notch signaling was inhibited in the mouse model of bleomycin induced dermal fibrosis and in tight-skin-1 mice by the γ-secretase inhibitor DAPT and by overexpression of a Notch-1 antisense construct.
Notch signaling is activated in SSc in vivo with accumulation of the NICD and increased transcription of the target gene hes-1. Overexpression of a Notch antisense construct prevented bleomycin-induced fibrosis and hypodermal thickening in tight-skin 1 mice. Potent anti-fibrotic effects were also obtained by treatment with DAPT. In addition to prevention of fibrosis, targeting Notch signaling resulted in almost complete regression of pre-established experimental fibrosis.
We demonstrate that pharmacologic as well as genetic inhibition of Notch signaling exerts potent anti-fibrotic effects in different murine models of SSc. These findings might have direct translational implications because different inhibitors of the γ-secretase complex are available and yielded promising results in cancer trials.
PMCID: PMC5175482  PMID: 21312186
3.  Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study 
PLoS ONE  2016;11(10):e0163894.
Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc.
In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis.
Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide<80% predicted (65%), DU (34%), cardiac involvement (32%), FVC<80% predicted (31%), increased PAPsys>40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis.
In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to ‘widen' the still very narrow ‘window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.
PMCID: PMC5051961  PMID: 27706206
4.  Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis 
Annals of the Rheumatic Diseases  2016;75(10):1743-1748.
Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc.
We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied.
From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors.
Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care.
PMCID: PMC5036205  PMID: 27016052
Systemic Sclerosis; Outcomes research; Epidemiology
5.  Efficient therapy of ischaemic lesions with VEGF121-fibrin in an animal model of systemic sclerosis 
Annals of the Rheumatic Diseases  2015;75(7):1399-1406.
In systemic sclerosis (SSc), chronic and uncontrolled overexpression of vascular endothelial growth factor (VEGF) results in chaotic vessels, and intractable fingertip ulcers. Vice versa, VEGF is a potent mediator of angiogenesis if temporally and spatially controlled. We have addressed this therapeutic dilemma in SSc by a novel approach using a VEGF121 variant that covalently binds to fibrin and gets released on demand by cellular enzymatic activity. Using University of California at Davis (UCD)-206 chickens, we tested the hypothesis that cell-demanded release of fibrin-bound VEGF121 leads to the formation of stable blood vessels, and clinical improvement of ischaemic lesions.
Ninety-one early and late ischaemic comb and neck skin lesions of UCD-206 chickens were treated locally with VEGF121-fibrin, fibrin alone, or left untreated. After 1 week of treatment the clinical outcome was assessed. Angiogenesis was studied by immunofluorescence staining of vascular markers quantitatively analysed using TissueQuest.
Overall, 79.3% of the lesions treated with VEGF121-fibrin showed clinical improvement, whereas 71.0% of fibrin treated controls, and 93.1% of untreated lesions deteriorated. This was accompanied by significantly increased growth of stable microvessels, upregulation of the proangiogenic VEGFR-2 and its regulator TAL-1, and increase of endogenous endothelial VEGF expression.
Our findings in the avian model of SSc suggest that cell-demanded release of VEGF121 from fibrin matrix induces controlled angiogenesis by differential regulation of VEGFR-1 and VEGFR-2 expression, shifting the balance towards the proangiogenic VEGFR-2. The study shows the potential of covalently conjugated VEGF-fibrin matrices for the therapy of ischaemic lesions such as fingertip ulcers.
PMCID: PMC4766736  PMID: 26362758
Systemic Sclerosis; Treatment; Outcomes research
6.  Treatment of systemic sclerosis: is there any hope for the future? 
RMD Open  2016;2(2):e000260.
PMCID: PMC4947768  PMID: 27486527
Systemic Sclerosis; Outcomes research; Autoimmunity; Treatment
7.  Efficient therapy of ischemic lesions with VEGF121-fibrin in an animal model of systemic sclerosis 
Annals of the rheumatic diseases  2015;75(7):1399-1406.
In systemic sclerosis (SSc), chronic and uncontrolled over-expression of vascular endothelial cell growth factor (VEGF) results in chaotic vessels, and intractable fingertip ulcers. Vice versa, VEGF is a potent mediator of angiogenesis if temporally and spatially controlled available. We have addressed this therapeutic dilemma in SSc by a novel approach using a VEGF121 variant that covalently binds to fibrin and gets released on demand by cellular enzymatic activity. Using UCD-206 chickens, we tested the hypothesis that cell-demanded release of fibrin-bound VEGF121 leads to the formation of stable blood vessels, and clinical improvement of ischemic lesions.
Ninety-one early and late ischemic comb and neck skin lesions of UCD-206 chickens were treated locally with VEGF121-fibrin, fibrin alone, or left untreated. After one week of treatment the clinical outcome was assessed. Angiogenesis was studied by immunofluorescence staining of vascular markers quantitatively analysed using Tissuequest®.
Over all, 79.3% of the lesions treated with VEGF121-fibrin showed clinical improvement, whereas 71.0% of fibrin treated controls, and 93.1% of untreated lesions deteriorated. This was accompanied by significantly increased growth of stable microvessels, up-regulation of the pro-angiogenic VEGFR-2 and its regulator TAL-1, and increase of endogenous endothelial VEGF expression.
Our findings in the avian model of SSc suggest that cell-demanded release of VEGF121 from fibrin matrix induces controlled angiogenesis by differential regulation of VEGFR-1 and VEGFR-2 expression, shifting the balance towards the pro-angiogenic VEGFR-2. The study shows the potential of covalently conjugated VEGF-fibrin matrices for the therapy of ischemic lesions such as fingertip ulcers.
PMCID: PMC4766736  PMID: 26362758
systemic sclerosis; ischemic ulcers; angiogenesis; therapy; UCD-206 chicken
8.  Outcome Measures for Clinical Trials in Interstitial Lung Diseases 
The chronic fibrosing idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous pulmonary parenchymal disorders described by radiologic and histological patterns termed usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). These include idiopathic pulmonary fibrosis (IPF) and those related to connective tissue disease (CTD) and are associated with substantial morbidity and mortality. Beyond the importance of establishing an appropriate diagnosis, designing optimal clinical trials for IIPs has been fraught with difficulties in consistency of clinical endpoints making power analyses, and the establishment of efficacy and interpretation of results across trials challenging.
Preliminary recommendations, developed by rigorous consensus methods, proposed a minimum set of outcome measures, a ‘core set’, to be incorporated into future clinical trials (Saketkoo et al, THORAX. 2014.). This paper sets out to examine the candidate instruments for each domain (Dyspnea, Cough, Health Related Quality of Life, Imaging, Lung Physiology and Function, Mortality). Candidate measures that were not selected as well as measures that were not available for examination at the time of the consensus process will also be discussed.
PMCID: PMC4806861  PMID: 27019654
Chronic fibrosing; connective tissue disease related interstitial lung disease; idiopathic interstitial pneumonia; idiopathic pulmonary fibrosis; rheumatoid arthritis; scleroderma; systemic sclerosis
9.  Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards 
Rheumatology (Oxford, England)  2014;54(1):144-151.
Objective. SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc.
Methods. Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9.
Results. By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs.
Conclusion. Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed.
PMCID: PMC4269793  PMID: 25125594
systemic sclerosis; clinical trials; points to consider
10.  Rapid Growth of Lung Nodules due to Combined Pulmonary Vasculitis, Silicoanthracosis, and Chondrocalcinosis 
Canadian Respiratory Journal  2016;2016:9254374.
Background. Silicoanthracosis is a pneumoconiosis due to occupational inhalation of silica and carbon dusts. Clinically, it can be associated with vasculitis or rheumatoid arthritis. In association with these diseases, silicoanthracosis can present within the lung with multiple pulmonary nodules which, as a differential diagnosis, can mimic metastatic disease or multiple abscesses. Case Presentation. We present the case of a 62-year old former pit worker with pulmonary nodules, chondrocalcinosis due to calcium pyrophosphate deposition (CPPD), and a history of renal cancer. Within a short period of time, pulmonary nodules grew rapidly. Thoracoscopically, the resected lung specimen revealed silicoanthracosis associated with small-to-medium-size vasculitis in the presence of antineutrophil cytoplasmatic autoantibodies (c-ANCA). Conclusion. Pulmonary silicoanthracotic lesions on the base of ANCA-associated vasculitis and CPPD arthritis can rapidly grow. A mutual correlation between silicoanthracosis, ANCA-associated vasculitis, and CPPD seems possible. Apart from this, consideration of metastatic disease should be obligatory in patients with a history of cancer at the same time being immunosuppressed.
PMCID: PMC4958431  PMID: 27478398
11.  Pulmonary Hypertension in Patients with Chronic Fibrosing Idiopathic Interstitial Pneumonias 
PLoS ONE  2015;10(12):e0141911.
Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies.
We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH-IIP).
Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH-IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP.
Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival.
Trial Registration NCT01347216
PMCID: PMC4667900  PMID: 26630396
12.  Cardiac arrhythmias and conduction defects in systemic sclerosis 
Rheumatology (Oxford, England)  2013;53(7):1172-1177.
Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e. related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations.
PMCID: PMC4065005  PMID: 24241036
systemic sclerosis; arrhythmias; conduction defects; cardiac involvement; mortality
13.  Systemic Sclerosis Classification Criteria: Developing methods for multi-criteria decision analysis with 1000Minds 
Journal of clinical epidemiology  2014;67(6):706-714.
Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to: develop an instrument for collating case-data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement between experts on the probability that cases were classified as SSc.
Study Design and Setting
A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank-ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and re-ranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICC).
Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14–22), finger-tip lesions (9–21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud’s phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7) and puffy fingers (5). The ICC across experts was 0.73 (95%CI 0.58,0.86) and improved to 0.80 (95%CI 0.68,0.90).
Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (23 to 14) and weighted. Our methods reflect the rigors of measurement science, and serves as a template for developing classification criteria.
PMCID: PMC4134523  PMID: 24721558
Scleroderma; Systemic Sclerosis; Decision Analysis; Forced-Choice; Classification Criteria; Conjoint Analysis; Sensibility
14.  Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population 
Rheumatology (Oxford, England)  2015;54(7):1262-1269.
Objective. The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort.
Methods. Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables.
Results. Based on our selection criteria, 1476 patients were included in the analysis; 87% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of <30 mmHg as reference, the hazard ratio (HR) for death was 1.67 (95% CI 0.92, 2.96) if the index sPAP was between 30 and 36 mmHg, 2.37 (95% CI 1.14, 4.93) for sPAP between 36 and 40 mmHg, 3.72 (95% CI 1.61, 8.60) for sPAP between 40 and 50 mmHg and 9.75 (95% CI 4.98, 19.09) if sPAP was >50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95% CI 1.035, 3.247) and HR 0.973 (95% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95% CI 1.91, 4.78) for sPAP ≥36 mmHg.
Conclusion. An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization.
PMCID: PMC4473765  PMID: 25596413
systemic sclerosis; tricuspid regurgitant jet velocity; systolic pulmonary arterial pressure; pulmonary hypertension; survival
15.  Borderline pulmonary arterial pressure in systemic sclerosis patients: a post-hoc analysis of the DETECT study 
Patients with mean pulmonary artery pressures (mPAP) of 21 to 24 mm Hg have a so-called borderline elevation of mPAP (BoPAP)—a condition thought to represent early-stage pulmonary arterial vasculopathy. Based on the DETECT study, this post-hoc analysis examined patient characteristics of systemic sclerosis (SSc) patients with normal mPAP, BoPAP and elevated mPAP, fulfilling pulmonary arterial hypertension (PAH) criteria.
Adult patients with a duration of SSc more than 3 years, a diffusing capacity of the lung for carbon monoxide less than 60% predicted, and no previous diagnosis of any form of pulmonary hypertension (PH) underwent screening tests followed by right heart catheterization. Subjects were divided into three groups: normal mPAP, BoPAP, and PAH. Exploratory comparative and binary logistic regression analyses were performed for the BoPAP versus normal mPAP and PAH versus BoPAP groups.
Of 244 patients evaluated, 148 (60%) had normal mPAP, 36 (15%) had BoPAP, and 60 (25%) had definite PAH. Univariable logistic regression (ULR) showed the mean tricuspid regurgitation velocity in patients with BoPAP to be intermediate between normal mPAP and PAH. In the ULR analyses BoPAP versus normal mPAP and PAH versus BoPAP, the statistically significant predictors were, amongst others: demographic, clinical, pulmonary function, echocardiographic and hemodynamic variables.
In this exploratory post-hoc analysis of the DETECT study population patients with BoPAP could be distinguished from patients with normal mPAP and PAH, and it appears that BoPAP may be an intermediate stage on the continuum between normal PA pressures and PAH.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0493-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4299685  PMID: 25491468
16.  Recommendations for Screening and Detection of Connective-Tissue Disease Associated Pulmonary Arterial Hypertension 
Arthritis and rheumatism  2013;65(12):10.1002/art.38172.
Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTD). Previous recommendations developed as part of larger efforts in PAH did not provide detailed recommendations for patients with CTD-PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-PAH.
We performed a systematic review for the screening and diagnosis of PAH in CTD by searching the literature. Using the RAND/UCLA methodology, we developed case scenarios followed by 2 stages of voting—first international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario and then the experts met in a face-to-face meeting to discuss and resolve discrepant votes to arrive at consensus recommendations.
The key recommendations state that patients with systemic sclerosis (SSc) should be screened for PAH. In addition, mixed connective tissue diseases (MCTD) or other CTD’s with scleroderma features should also be screened for PAH (scleroderma-spectrum disorder). Initial screening evaluation in patients with SSc and scleroderma-spectrum disorders include pulmonary function test (PFT) including diffusion capacity carbon monoxide (DLCO), transthoracic echocardiogram (TTE), and NT- Pro BNP. In SSc and spectrum disorders, TTE and PFT should be performed on annual basis. The full screening panel (TTE, PFT, and NT-ProBNP) should be performed as soon as any new signs or symptoms are present.
We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-PAH. It is our hope that these recommendations will lead to earlier detection of CTD-PAH and ultimately improve patient outcomes.
PMCID: PMC3883571  PMID: 24022584
Pulmonary hypertension; pulmonary arterial hypertension; connective tissue diseases; systemic sclerosis; recommendations; guidelines
17.  Classification Criteria for Systemic Sclerosis: An ACR-EULAR Collaborative Initiative 
Arthritis and rheumatism  2013;65(11):2737-2747.
The 1980 classification criteria for systemic sclerosis (SSc) lack sensitivity in early SSc and limited cutaneous SSc. A joint ACR-EULAR committee was established to develop new classification criteria for SSc.
Using consensus methods, 23 candidate items were arranged in a multi-criteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items, and simplifying weights. The system was tested by: a) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders; b) validating against the combined view of a group of experts on a set of cases with or without SSc.
Skin thickening of the fingers extending proximal to the MCPs is sufficient to be classified as SSc, if that is not present, seven additive items apply with varying weights for each: skin thickening of the fingers, finger tip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ARA classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc by the 1980 ARA criteria were classified with the new criteria, and several additional cases were now considered to be SSc.
The ACR-EULAR classification criteria for SSc performed better than the 1980 ARA Criteria for SSc and should allow for more patients to be classified correctly as SSc.
PMCID: PMC3930146  PMID: 24122180
Systemic Sclerosis; Scleroderma; Classification Criteria; Conjoint Analysis; Multi Criteria Additive Point System; Validation; ACR-EULAR
18.  β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis 
Annals of the rheumatic diseases  2012;71(5):761-767.
Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis.
Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4′,6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis.
The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis.
The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.
PMCID: PMC3951949  PMID: 22328737
19.  Items for developing revised classification criteria in systemic sclerosis: results of a consensus exercise with the ACR/EULAR working committee for classification criteria in systemic sclerosis 
Arthritis care & research  2012;64(3):351-357.
Classification criteria for systemic sclerosis (SSc) are being updated.
To select a set of items potentially useful for the classification of SSc using consensus procedures including the Delphi and nominal group techniques (NGT).
Items were identified through two independent consensus exercises performed by the Scleroderma Clinical Trials Consortium (SCTC) and the EULAR Scleroderma Trials and Research Group (EUSTAR). The first-round items from both exercises were collated and redundancies were removed leaving 168 items. A 3-round Delphi exercise was performed using a 1–9 scale (1=completely inappropriate and 9=completely appropriate) and a consensus meeting using NGT. During the last Delphi, the items were ranked on a 1–10 scale.
Round 1: 106 experts rated the 168 items. Those with a median score <4 were removed, resulting in a list of 102 items. Round 2: The items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n=16), resulting in 23 items. Round 3: SSc experts (n=26) then individually scored each of the 23 items in a last Delphi round, using an appropriateness score (1–9) and ranking their 10 most appropriate items for classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern and Raynaud’s phenomenon ranked highest in the final list that also included items indicating internal organ involvement.
The Delphi exercise and NGT resulted in a set of 23 items for classification of SSc which will be assessed for their discriminative properties in a prospective study.
PMCID: PMC3288452  PMID: 22052558
Delphi technique; nominal group technique; systemic sclerosis; scleroderma; classification; classification criteria
20.  Molecular targets for therapy in systemic sclerosis 
Fibrogenesis & Tissue Repair  2012;5(Suppl 1):S19.
Despite significant advances have been made in the recent years regarding organ-specific therapies, there is no approved 'disease-modifying' antifibrotic drug for systemic sclerosis (SSc) available to date. Although non-selective immunosuppressive agents are routinely used to treat patients with SSc, large well-controlled studies are lacking for almost all immunosuppressive agents and further evidence is required for long-term beneficial effects of these drugs. Considering these facts about immunosuppressive agents in SSc and also considering the high mortality of SSc, other therapeutic strategies are urgently needed. Recently an important role of the 5-hydroxytryptamine (5-HT: serotonin) pathway in fibrosis was reported. In this review, we discuss the role of 5-HT in fibrosis and therapeutic potential of this molecule. Besides 5-HT, there are a number of promising targets that have been extensively characterized in recent years. For many of these molecular targets, modifiers are readily available for clinical studies, and often these modifiers are used already in clinical use for other diseases. Results from these studies will show, in how far the promising preclinical results for novel antifibrotic strategies can be translated to clinical practice.
PMCID: PMC3368787  PMID: 23259845
21.  Systemic Sclerosis 2011 
PMCID: PMC3332200  PMID: 22577388
22.  Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group 
Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known.
This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively.
Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients.
Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed.
PMCID: PMC3392836  PMID: 22348608
23.  International cohort study of 73 anti-Ku-positive patients: association of p70/p80 anti-Ku antibodies with joint/bone features and differentiation of disease populations by using principal-components analysis 
An international cohort study of 73 anti-Ku-positive patients with different connective tissue diseases was conducted to differentiate the anti-Ku-positive populations of patients based on their autoantibody profile and clinical signs/symptoms and to establish possible correlations between antibodies against Ku p70 and Ku p80 with autoimmune diseases.
Sera of anti-Ku-positive patients were collected from six European centers and were all secondarily tested (in the reference center); 73 were confirmed as positive. Anti-Ku antibodies were detected with counter-immunoelectrophoresis (CIE), line immunoassay (LIA), and immunoblot analyses. All clinical and laboratory data were follow-up cumulative data, except for anti-Ku antibodies. Statistical analyses were performed by using R (V 2.12.1). The Fisher Exact test was used to evaluate the association between anti-Ku antibodies and diagnosis, gender, clinical signs, and other observed antibodies. The P values were adjusted for multiple testing. Separation of disease populations based on the presence of antibodies and clinical signs was investigated by principal-components analysis, which was performed by using thr// R's prcomp function with standard parameters.
A 16% higher prevalence of anti-Ku p70 was found over anti-Ku p80 antibodies. In 41 (57%) patients, a combination of both was detected. Five (7%) patients, who were CIE and/or LIA anti-Ku positive, were negative for both subsets, as detected with the immunoblot; 31% of the patients had undifferentiated connective tissue disease (UCTD); 29% had systemic sclerosis (SSc); 18% had systemic lupus erythematosus (SLE); 11% had rheumatoid arthritis; 7% had polymyositis; and 3% had Sjögren syndrome.
A significant positive association was found between female patients with anti-Ku p70 and joint/bone features, and a significant negative association was found between female patients with anti-Ku p80 only and joint/bone features (P = 0.05, respectively). By using the first and the third components of the principal-component analysis (PCA) with 29 parameters evaluated, we observed that the anti-Ku-positive population of UCTD patients had overlapping parameters, especially with SLE, as opposed to SSc, which could be helpful in delineating UCTD patients.
PMCID: PMC3392788  PMID: 22226402
24.  Role of MicroRNAs in Fibrosis 
Fibrosis is the leading cause of organ dysfunction in diseases such as systemic sclerosis, liver cirrhosis, cardiac fibrosis, progressive kidney disease, and idiopathic pulmonary fibrosis. The hallmark of fibrosis is tissue remodeling with excess deposition of extracellular matrix components, predominantly collagens. Different cell types, cytokines, growth factors, and enzymes interact in complex pathogenic networks with myofibroblasts playing a pivotal role. MicroRNAs are small non-coding RNAs acting as negative regulators of gene expression at the post-transcriptional level. MicroRNAs have been associated with many basic cellular processes as well as with a wide spectrum of diseases, most notably cancer. This review provides a comprehensive overview of microRNAs regulating profibrotic pathways and extracellular matrix synthesis. The potential of miRNA for targeted therapeutic approaches in fibrotic disorders is also discussed.
PMCID: PMC3396185  PMID: 22802911
Fibrosis; fibroblasts; microRNA (miRNA)-mediated gene regulation regulation; transforming growth factor-beta (TGF-β); connective tissue growth factor (CTGF); extracellular matrix (ECM); epithelial-to-mesenchymal transition (EMT); signaling pathways; antagomirs.
25.  Systemic sclerosis-associated pulmonary hypertension: why disease-specific composite endpoints are needed 
Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc). In clinical trials PAH-SSc has been grouped with other forms, including idiopathic PAH. The primary endpoint for most pivotal studies was improvement in exercise capacity. However, composite clinical endpoints that better reflect long-term outcome may be more meaningful. We discuss potential endpoints and consider why the same measures may not be appropriate for both idiopathic PAH and PAH-SSc due to inherent differences in clinical outcome and management strategies of these two forms of PAH. Failure to take this into account may compromise progress in managing PAH in SSc.
PMCID: PMC3218892  PMID: 21699746

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