L. Czirják

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

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.

European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria

Objective: To further assess the construct validity of the three European Scleroderma Study Group (EScSG) preliminary activity indices for systemic sclerosis (SSc): for SSc as a whole, for diffuse SSc (dcSSc), and for limited SSc (lcSSc). Methods: 30/290 SSc clinical charts collected for the EScSG study used to develop activity criteria for SSc were selected and sent to four clinical experts in SSc. The experts ranked the charts from 1 to 30 (1=lowest activity, 30=highest activity). The relationships among the ranks given by each investigator and each of the three scores, and between any two of the ranks were investigated. Results: A consistently significant correlation (rs=0.530–0.712) was found between the ranks given by each of the four investigators and the index for the entire patient group. A similar level of agreement was detected between each couple of the four experts (rs=0.428–0.720). Moreover, the ranks given in patients with an index >3 were significantly higher than those given for patients with an index ⩽3. This cut off point had previously been shown to best discriminate patients with active disease. Conclusions: Of the originally developed activity indexes, the whole series index has been externally validated. The index comprises the first preliminary, but necessary, groundwork to improve the concept of disease activity in SSc, which is still ill defined. It can be used as a preliminary activity index in clinical investigational studies.

The challenge of early systemic sclerosis for the EULAR Scleroderma Trial and Research group (EUSTAR) community. It is time to cut the Gordian knot and develop a prevention or rescue strategy

Early diagnosis of systemic sclerosis (SSc) may allow the start of treatment that could slow disease progression. For this reason early diagnosis of the disease is of pivotal importance. However, the lack of diagnostic criteria and valid predictors significantly limit patient evaluation and the use of potentially effective drugs in the earliest phase of SSc. Early SSc may be suspected on the basis of Raynauds phenomenon, puffy fingers, autoantibodies and SSc capillaroscopic pattern. In practice, the aim is to have criteria for the diagnosis of very early SSc. The criteria that are proposed are obviously provisional and need to be validated: (a) initially through a Delphi technique; (b) thereafter perhaps using already available datasets; but (c) of critical importance, through prospective studies. Only after prospective studies can these potential criteria be considered validated. The consensus on criteria for the classification of very early SSc might be part of the evolving EULAR/ACR project of reclassification of SSc.

European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres

OBJECTIVE To investigate the existence of differences among European referral centres for systemic sclerosis (SSc) in the pattern of attendance and referral and in the clinical and therapeutical approaches. METHODS In 1995 the European Scleroderma Study Group initiated a multicentre prospective one year study whose aim was to define the disease activity criteria in SSc. During the study period each participating European centre was asked to enrol consecutive patients satisfying American College of Rheumatology criteria for SSc and to fill out for each of them a standardised clinical chart. Patients from various centres were compared and differences in epidemiological, clinical, and therapeutical aspects were analysed. RESULTS Nineteen different medical research centres consecutively recruited 290 patients. The patients could be divided into two subgroups: 173 with the limited (lSSc) and 117 with the diffuse (dSSc) form of the disease. The clinical and serological findings for the series of 290 patients seemed to be similar to data previously reported. However, when the data were analysed to elicit any differences between the participating centres, a high degree of variability emerged, in both epidemiological and clinical features and in the diagnostic and therapeutic approaches to the disease. CONCLUSIONS The clinical approach to SSc, not only in different countries but also in different centres within the same country, is not yet standardised. To overcome this problem, it will be necessary for the scientific community to draw up a standardised procedure for the management of patients with SSc. This would provide a common research tool for different centres engaged in research on this complex disease.

Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database

Background: Systemic sclerosis (SSc) is a vasculopathy with increased tissue deposition of collagen. The aetiology is unknown. Genetic and environmental susceptibility factors have been implicated. It is unknown whether disease presentation varies within Europe. Aims and Methods: The baseline data of all SSc patients entered in the EULAR Scleroderma Trials and Research (EUSTAR) database up to April 2007 were analysed for geographical differences with regard to organ involvement, and geographical clusters with regard to clinical subsets (diffuse vs limited SSc) and autoantibodies (anticentromere vs anti-Scl70). Results: 3661 patients from 79 centres in 62 cities and 23 countries were analysed. There was no clear trend between geographical coordinates and SSc subsets, although there appeared to be an increased prevalence of Scl70 in the more eastern centres. There was no association between geographical longitude or latitude and the age at the onset of Raynaud’s phenomenon or the onset of non-Raynaud’s symptoms. There was also a trend for the more eastern centres to care for patients with a higher prevalence of more severe organ manifestations (pulmonary arterial hypertension, cardiac involvement). Between different centres within one city there was a large variability in the frequency of organ complications. Conclusion: This analysis suggests that eastern centres care for more severe SSc manifestations in Europe. Large differences in patient referral account for a large local variability of SSc presentations and preclude the identification of genetic or environmental factors.

Lack of association between three vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients

Introduction: Systemic sclerosis (SSc) is characterised by disturbed vessel morphology and an overproduction of vascular endothelial growth factor (VEGF). The VEGF gene located on chromosome 6p21.3 has several polymorphisms. Objective: To test the hypothesis that disturbed angiogenesis may be related to the genetic background of the VEGF gene. Materials and methods: EUSTAR centres included European Caucasian patients with SSc and matched controls with osteoarthritis. The VEGF gene was genotyped by polymerase chain reaction, followed by restriction enzyme analysis. The 634 C/T and 936 C/G mutations and an 18-base pair insertion/deletion at −2549 of the VEGF promoter region were tested. Results: 416 patients with SSc and 249 controls were included in the study population. Of the patients with SSc, 42% had a diffuse cutaneous subtype, 16% had increased pulmonary arterial pressure and 61% had decreased carbon monoxide diffusion capacity. The genotype frequencies in the patients with SSc and in controls were in Hardy–Weinberg equilibrium. The allele and genotype frequencies of the polymorphisms did not differ between patients with SSc and controls. No association was found between these polymorphisms and disease phenotypes. Conclusion: This study shows that there is no association between the three selected functional VEGF polymorphisms and SSc.

Standardization of the Modified Rodnan Skin Score for Use in Clinical Trials of Systemic Sclerosis

The modified Rodnan skin score (mRSS) is a measure of skin thickness and is used as a primary or secondary outcome measure in clinical trials of systemic sclerosis (scleroderma). This state-of-art review provides a historical perspective of the development of the mRSS, summarizes the performance of mRSS as an outcome measure, provides guidance on assessing mRSS, and makes recommendations for incorporation of the mRSS into clinical trials.

Points to consider for skin ulcers in systemic sclerosis

This article discusses points to consider when undertaking a clinical trial to test therapy for skin ulcers in SSc. A validated definition of skin ulcers should be used if available. Defining a uniform SSc patient population, including consideration of disease duration, history of digital ulcers and capillaroscopic patterns, is important. Excluding confounding factors such as infection, calcinosis and trauma should be strongly considered, or at least accounted for, in defining patients. Outcome measures such as time to healing, prevention of new ulcers, function, pain and objective measures such as US, laser Doppler and thermography can be considered as outcome measures, although their validation has not yet been achieved and efforts may be needed to validate them before use. Likewise, biomarkers should be considered or consideration should be given to storing serum, plasma or cells for possible future analysis. A pre-planned analysis is important and should include consideration of missing data.

OP0061 Update of Eular Recommendations for the Treatment of Systemic Sclerosis

Objectives The aim was to update the 2009 EULAR recommendations for the treatment of systemic sclerosis (SSc) [1] with a distinct focus on new therapeutic aspects. Methods Revision and update of the previous recommendations were performed according to the EULAR standard operating procedures. The task force consisted of 30 SSc experts from Europe and USA, two patients nominated by the pan-European patients association FESCA, a clinical epidemiologist and 3 fellows for systematic literature research. All centers from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select research questions concerning SSc treatment using a Delphi approach. A set of 46 research questions addressing 26 different interventions was selected for systematic literature research. The new recommendations were developed in a meeting, based on the available evidence while using a consensus procedure. Results Sixteen recommendations were developed (instead of 14 in 2009) which address treatments of several SSc-related organ complications: Raynauds phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement. Compared with the 2009 recommendations, the 2015 recommendations include phosphodiestase-5 (PDE5) inhibitors in the treatment of SSc-related RP and DUs, riociguat and new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE5 inhibitors for SSc-related PAH. The new recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressing SSc were added. In addition, the statement regarding sitaxentan for PAH was removed, because it was withdrawn from the market. A web-based internal evaluation of the new recommendations revealed high level of approval among task force members (average score >7 out of maximum 9) for all statements except the one regarding fluoxetine for RP (average score of 6,1). In addition, several comments regarding other treatments addressed in research questions and suggestions for the future SSc research agenda were formulated by the experts. Conclusions These updated and improved, data- and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations will also facilitate the directions for future clinical research in SSc. References Kowal-Bielecka et al. Ann Rheum Dis 2009;68:620) Acknowledgements The project is funded by a research grant of EULAR to the EUSTAR SSc recommendation group. All contributing experts will be listed as full coauthors on the respective presentations and publications. Disclosure of Interest O. Kowal-Bielecka Speakers bureau: Abbvie, Actelion, Pfizer, Roche, J. Fransen: None declared, J. Avouac: None declared, M. Becker Consultant for: Actelion, A. Kulak: None declared, Y. Allanore Consultant for: Bayer Pharma, Actelion, Pfizer, Sanofi-Aventis, CSL Behring, Roche, O. Distler Consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation., L. Czirjak Consultant for: MSD, Pfizer, Roche, Abbvie, UCB, BMS, Servier, Medac, Richter, Egis, C. Denton Grant/research support from: Actelion, CSL Behring, Novartis, Consultant for: Actelion, GSK, Bayer, Inventiva, Takeda, K. Fligelstone: None declared, J. Welling: None declared, U. Mueller-Ladner Grant/research support from: EULAR grant

There is a need for new systemic sclerosis subset criteria. A content analytic approach

Objectives. Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. Methods. We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. Results. Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). Conclusions. We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).