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Arthritis & Rheumatism | 2013

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

Frank J. A. van den Hoogen; Dinesh Khanna; Jaap Fransen; Sindhu R. Johnson; Murray Baron; Alan Tyndall; Marco Matucci-Cerinic; Raymond P. Naden; Thomas A. Medsger; Patricia Carreira; Gabriela Riemekasten; Philip J. Clements; Christopher P. Denton; Oliver Distler; Yannick Allanore; Daniel E. Furst; Armando Gabrielli; Maureen D. Mayes; Jacob M van Laar; James R. Seibold; László Czirják; Virginia D. Steen; Murat Inanc; Otylia Kowal-Bielecka; Ulf Müller-Ladner; Gabriele Valentini; Douglas J. Veale; Madelon C. Vonk; Ulrich A. Walker; Lorinda Chung

OBJECTIVE The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS Using consensus methods, 23 candidate items were arranged in a multicriteria 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 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.


American Journal of Respiratory and Critical Care Medicine | 2008

Interstitial Lung Disease in Systemic Sclerosis A Simple Staging System

Nicole Goh; Sujal R. Desai; Srihari Veeraraghavan; David M. Hansell; Susan J. Copley; Toby M. Maher; Tamera J. Corte; Clare R. Sander; Jonathan Ratoff; Anand Devaraj; Gracijela Bozovic; Christopher P. Denton; Carol M. Black; Roland M. du Bois; Athol U. Wells

RATIONALE In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain. OBJECTIVES To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT. METHODS The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data. MEASUREMENTS AND MAIN RESULTS Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC >or= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P < 0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P < 0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly < 20% or clearly > 20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60). CONCLUSIONS An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.


Annals of the Rheumatic Diseases | 2013

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Frank J. A. van den Hoogen; Dinesh Khanna; Jaap Fransen; Sindhu R. Johnson; Murray Baron; Alan Tyndall; Marco Matucci-Cerinic; Raymond P. Naden; Thomas A. Medsger; Patricia Carreira; Gabriela Riemekasten; Philip J. Clements; Christopher P. Denton; Oliver Distler; Yannick Allanore; Daniel E. Furst; Armando Gabrielli; Maureen D. Mayes; Jacob M van Laar; James R. Seibold; László Czirják; Virginia D. Steen; Murat Inanc; Otylia Kowal-Bielecka; Ulf Müller-Ladner; Gabriele Valentini; Douglas J. Veale; Madelon C. Vonk; Ulrich A. Walker; Lorinda Chung

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria 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 (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.


Annals of the Rheumatic Diseases | 2007

Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database

Ulrich A. Walker; A. Tyndall; László Czirják; Christopher P. Denton; Dominique Farge-Bancel; Otylia Kowal-Bielecka; Ulf Müller-Ladner; Chiara Bocelli-Tyndall; Marco Matucci-Cerinic

Background: Systemic sclerosis (SSc) is a multisystem autoimmune disease, which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment, the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004. Aims and methods: EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the American College of Rheumatology diagnostic criteria in participating centres. We aimed to characterise demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits. Results: In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were women. On multivariate analysis, scleroderma subsets (dcSSc vs lcSSc), antibody status and age at onset of Raynaud’s phenomenon, but not gender, were found to be independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis was more closely associated with clinical manifestations than were SSc subsets. Conclusion: dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction seemed to be superseded by an antibody-based classification in predicting some scleroderma complications. The EUSTAR MEDS database facilitates the analysis of clinical patterns in SSc, and contributes to the standardised assessment and monitoring of SSc internationally.


Annals of the Rheumatic Diseases | 2010

Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database

A. Tyndall; Bettina Bannert; Madelon C. Vonk; Paolo Airò; Franco Cozzi; Patricia Carreira; Dominique Farge Bancel; Yannick Allanore; Ulf Müller-Ladner; Oliver Distler; Florenzo Iannone; Raffaele Pellerito; Margarita Pileckyte; Irene Miniati; Lidia P. Ananieva; Alexandra Balbir Gurman; Nemanja Damjanov; Adelheid Mueller; Gabriele Valentini; Gabriela Riemekasten; Mohammed Tikly; Laura K. Hummers; Maria João Henriques; Paola Caramaschi; Agneta Scheja; Blaz Rozman; Evelien Ton; Gábor Kumánovics; Bernard Coleiro; Eva Feierl

Objectives To determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan–Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Results Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynauds phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.


Annals of the Rheumatic Diseases | 2009

EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR)

Otylia Kowal-Bielecka; R. Landewé; J. Avouac; S. Chwiesko; Irene Miniati; L. Czirják; P. Clements; Christopher P. Denton; D. Farge; Kim Fligelstone; I. Földvari; D.E. Furst; Ulf Müller-Ladner; J. Seibold; Richard M. Silver; Kazuhiko Takehara; B. Garay Toth; A. Tyndall; G. Valentini; F.H.J. van den Hoogen; F. Wigley; Marco Matucci-Cerinic

Purpose: The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc. Methods: To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres. Results: Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc were formulated. The final set includes the following recommendations: three on SSc-related digital vasculopathy (Raynaud’s phenomenon and ulcers); four on SSc-related pulmonary arterial hypertension; three on SSc-related gastrointestinal involvement; two on scleroderma renal crisis; one on SSc-related interstitial lung disease and one on skin involvement. Experts also formulated several questions for a future research agenda. Conclusions: Evidence-based, consensus-derived recommendations are useful for rheumatologists to help guide treatment for patients with SSc. These recommendations may also help to define directions for future clinical research in SSc.


Annals of the Rheumatic Diseases | 2011

Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial

Marco Matucci-Cerinic; Christopher P. Denton; Daniel E. Furst; Maureen D. Mayes; Vivien M. Hsu; Patrick H. Carpentier; Fredrick M. Wigley; Carol M. Black; Barri J. Fessler; Peter A. Merkel; Janet E. Pope; Nadera J. Sweiss; Mittie K. Doyle; Bernhard Hellmich; Thomas A. Medsger; Adele Morganti; Fabrice Kramer; Joseph H. Korn; James R. Seibold

Objectives Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for ‘RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis’) was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc. Methods This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU (‘cardinal ulcer’) to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety. Results Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean±standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment. Conclusions Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.


Heart | 2006

Systemic sclerosis associated pulmonary hypertension: improved survival in the current era

Mark Williams; Clare Das; Clive Handler; Mohammed R Akram; Joseph Davar; Christopher P. Denton; Cj Smith; Carol M. Black; John G. Coghlan

Objectives: To measure survival, haemodynamic function and functional class in patients with systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) in two treatment eras. Methods: Six year longitudinal study of 92 consecutive patients with SSc-PAH diagnosed by cardiac catheterisation. Data were collected both prospectively and retrospectively. Patients were given basic treatment (diuretics, digoxin, oxygen and warfarin). Where clinically indicated, a prostanoid was used as advanced treatment (historical control group). From 2002, the range of treatments available expanded to include bosentan, which was generally the preferred treatment (current treatment era group). Survival was measured from the date of diagnosis of pulmonary hypertension by cardiac catheterisation. Six minute walking distance and haemodynamic function were measured at the time of diagnosis and at least one month after treatment was started. Results: The historical control group comprised 47 patients, all of whom received basic treatment; 27 of these were also treated with prostanoids. The current treatment era group comprised 45 patients, all of whom received bosentan as preferred treatment. Kaplan–Meier survival in the historical control group was 68% at one year and 47% at two years. Survival in the current treatment era group was 81% and 71% (p  =  0.016) at one and two years, respectively. Pulmonary vascular resistance increased in the historical control group (by 147 dyn·s·cm−5), whereas in the current treatment era group, it remained stable over an average of nine months (decrease of 16 dyn·s·cm−5, p < 0.006). Conclusion: Survival of selected patients with SSc-PAH has improved in the current treatment era. In contrast to patients treated historically with basic drugs and prostanoids, patients treated in the current treatment era had improved survival associated with a lack of deterioration in cardiac haemodynamic function.


Current Opinion in Rheumatology | 2001

Transforming growth factor-beta and connective tissue growth factor: key cytokines in scleroderma pathogenesis.

Christopher P. Denton; David J. Abraham

Evidence for a role for members of the transforming growth factor &bgr; (TGF-&bgr;) family of cytokines in the pathogensis of systemic sclerosis and other fibrotic conditions is provided from studies of TGF-&bgr; protein and gene expression in lesional biopsy specimens, from altered responses of explanted fibroblasts to TGF-&bgr; stimulation which are associated with increased receptor expression on these cells and from genetic data linking TGF-&bgr; gene loci to the disease. Of the many effects of TGF-&bgr; on fibroblast properties induction of the connective tissue growth factor/Cyr61/NOV (CCN) family members, connective tissue growth factor (CTGF) may be particularly relevant to fibrosis. Moreover, systemic sclerosis (SSc) fibroblasts demonstrate constitutive over expression of CTGF that promotes migration, proliferation and matrix production. Studies of mechanisms regulating constitutive expression of CTGF by SSc fibroblasts are currently being undertaken and indicate that a TGF-&bgr; responsive element in the CTGF promoter is involved, although this appears to function independent of the Smad proteins, suggesting that other TGF-&bgr;–regulated pathways may be involved. TGF-neutralizing strategies have now been shown to abrogate many animal models of fibrosis, and will soon reach the clinical arena for SSc. These agents will further clarify the role of this ligand in initiating or sustaining fibrosis and offer the exciting possibility of targeted therapy for this disease.


Arthritis & Rheumatism | 2009

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen.

Markella Ponticos; Alan M. Holmes; Xu Shiwen; Patricia Leoni; Korsa Khan; Vineeth Rajkumar; Rachel K. Hoyles; George Bou-Gharios; Carol M. Black; Christopher P. Denton; David J. Abraham; Andrew Leask; Gisela Lindahl

OBJECTIVE Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor beta (TGFbeta) and is a mediator of some profibrotic effects of TGFbeta in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I alpha2) in this mouse model and in human pulmonary fibroblasts. METHODS Transgenic mice that were carrying luciferase and beta-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts. RESULTS In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by approximately 25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycin-treated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling. CONCLUSION Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation of Col1a2. Blocking strategies revealed the signaling mechanisms involved. These findings show CTGF to be a rational target for therapy in fibrotic diseases such as SSc.

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Carol M. Black

University College London

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Xu Shiwen

University College London

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Voon H. Ong

University College London

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Yannick Allanore

Paris Descartes University

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Dinesh Khanna

University of California

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Madelon C. Vonk

Radboud University Nijmegen

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Ariane L. Herrick

Manchester Academic Health Science Centre

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