Relationship between natural and infection-induced antibodies in systemic autoimmune diseases (SAD): SLE, SSc and RA.

Infection or vaccine-induced T cell-dependent immune response and the subsequent high-affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease-specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine-induced and disease-related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme-linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti-CS) and F4 fragment (anti-F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti-measles IgG and anti-dsDNA IgG/IgM autoantibodies were measured using commercial and in-house indirect ELISA tests. In all SAD groups the anti-measles IgG-seropositive cases showed significantly higher anti-CS IgG titers (P = 0·011). In anti-dsDNA IgG-positive SLE patients, we detected significantly higher levels of anti-CS and anti-F4 IgG nAAbs (P = 0·001 and < 0·001, respectively). Additionally, we found increased levels of IgM isotypes of anti-CS and anti-F4 nAAbs in anti-dsDNA IgM-positive SLE patients (P = 0·002 and 0·016, respectively). The association between IgG isotypes of pathogen- or autoimmune disease-related antibodies and the IgG nAAbs may underscore the immune response-inducible nature of the diseases investigated. The relationship between protective anti-dsDNA IgM and the IgM isotype of anti-F4 and anti-CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.

Differences associated with age at onset in early systemic sclerosis patients: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR) database.

OBJECTIVE: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years' duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. METHOD: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud's SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud's phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31-59, and ≥ 60 years. We performed descriptive and bivariate analyses. RESULTS: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud's. CONCLUSION: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice.

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).

Follow-up of serum KL-6 lung fibrosis biomarker levels in 173 patients with systemic sclerosis.

OBJECTIVES: A single-centre retrospective longitudinal study to investigate the predictive value of KL-6 serum levels for the outcome of interstitial lung fibrosis in a large systemic sclerosis (SSc) patient cohort. METHODS: ELISA tests for the mucin like glycoprotein KL-6 were performed in sera of 173 SSc patients. The clinical and laboratory data were evaluated by a standardised protocol of chest x-ray, lung function tests, echocardiography and high-resolution computed tomography. 158 patients were 29 ± 22 months later reinvestigated, 9 patients (2 lcSSc, 7 dcSSc) died from SSc-related causes, and 6 patients were lost to follow-up. RESULTS: Serum titer of KL-6 was negatively correlated with lung function parameters, independent of the time of investigation. There was a significantly higher probability of death among patients with high level of baseline KL-6. There was no statistically significant difference in the deterioration and improvement rates between groups with normal and elevated KL-6 level at study entry, even in patients in early phase of disease (disease duration <3 years). Serum levels of KL-6 significantly decreased in patients receiving cyclophosphamide treatment in spite of the fact that the spirometry results (FVC and DLCO) did not show a significant change. CONCLUSIONS: KL-6 can be used as a lung fibrosis severity marker, but its role as a marker for disease activity is questionable. Furthermore, following cyclophosphamide treatment serum KL-6 levels may decrease independently of the lung function parameters.

Prognostic value of N-terminal natriuretic peptides in systemic sclerosis: a single centre study.

OBJECTIVES: Cardiac involvement is an important determinant of prognosis in systemic sclerosis (SSc). The identification of patients with high risk is of great importance. Our aim was to investigate the diagnostic and prognostic value of circulating concentrations of N-terminal fragments of A- and B-type natriuretic peptides (NT-proANP and NT-proBNP) in patients with SSc. METHODS: We prospectively studied 144 patients with SSc and followed them up for five years. Blood was collected for natriuretic peptide measurement at the time of the yearly scheduled cardiological check-up. The occurrence of clinically significant cardiac disease was measured as the composite of pulmonary arterial hypertension, cardiac revascularisation, development of left ventricular dysfunction or death. RESULTS: Patients diagnosed with heart involvement during the study had significantly higher levels of NT-proANP and NT-proBNP (791.4 ± 379.9 pmol/l vs. 608.0 ± 375.8 pmol/l, p<0.05 and 183.1 ± 162.6 vs. 125.7 ± 117.5 pmol/l, p<0.05, respectively). Receiver-operator-characteristic analysis identified <822.5 pmol/l as the best NT-proANP and <154.5 pmol/l as the best NT-proBNP threshold (sensitivity 56.3%, specificity 79.5%, negative predictive value: 86.4% and sensitivity 50.0%, specificity 76.8%, negative predictive value: 83.7%, respectively). During the follow-up, lower NT-proANP levels were significantly associated with a longer event-free survival (p<0.05), similar but a non-significant trend regarding NT-proBNP levels was also shown (p=0.052). CONCLUSIONS: In our cohort, NT-proANP had a supplementary prognostic value for cardiac involvement in systemic sclerosis. In addition, the high negative predictive value of natriuretic peptides supports the more extensive use in identifying SSc patients with high risk of future cardiac involvement.

A three-year follow-up study of the development of joint contractures in 131 patients with systemic sclerosis.

OBJECTIVES: To analyse the correlation between the number of joint-contractures and other major clinical findings in a follow-up study of 131 patients with systemic sclerosis (SSc). METHODS: The range of motion of joints (ROM), HAQ-DI, and the major clinical characteristics were assessed. RESULTS: A high frequency of contractures (ROM<75% of the normal) were present at baseline in small joints of the hand (82%), wrists (75%), and shoulders (50%). ROM of the dominant side hand was significantly more decreased compared to the non-dominant side. The number of the upper extremity contractures correlated positively with ESR (p<0.01), CRP (p<0.01), HAQ-DI (p<0.01), and negatively with forced vital capacity (FVC) (p<0.05). The number of contractures was not significantly different in cases with early (≤ 4 years) and late disease duration in both the limited and diffuse subgroups. During the three-year follow-up period, an increase in the number of joint contractures (ROM<75%) was associated with an increase of ESR, modified Rodnan's skin score, and the European Scleroderma Study Group Activity Index by multiple linear regression analysis. Univariate analysis over a six-year period demonstrated poor outcome in patients with more than ten contractures, or more than four contractures of unilateral hand-joints. CONCLUSIONS: Contractures predominantly develop during the early years following disease onset in both SSc subgroups. Inflammation and skin-involvement are significant contributing factors for the development of contractures. The dominant hand may be more pronouncedly impaired compared to the non-dominant side. A high number of joint-contractures might be an unfavourable prognostic factor in SSc.

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein-Barr nuclear antigen 1 and its aa35-58 or aa398-404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis.

Several studies suggest that infection by Epstein-Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti-Epstein-Barr nuclear antigen 1 (EBNA)-1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)-DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA-DRB1*15:01 carrier state and the serum titres against the whole EBNA-1 and its small fragments aa35-58 and aa398-404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA-DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman-based assay. The serum concentrations of antibodies to EBNA-1 and its aa35-58 or aa398-404 fragments were determined using a commercial assay (ETI-EBNA-G) and home-made enzyme-linked immunosorbent assays, respectively. The serum concentration of anti-EBNA-1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA-DRB1*15:01 carriers and non-carriers. Furthermore, titres of antibodies against the aa35-58 EBNA-1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398-404 EBNA-1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti-EBNA-1 IgG titres are HLA-DRB1*15:01-independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398-404 fragment are characteristic for SLE.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group.

OBJECTIVE: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). METHODS: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. RESULTS: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. CONCLUSION: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres.

OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

Overlap of coronary disease and pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc). Symptoms of coronary artery disease (CAD) and PAH are closely related and cardiac catheterisation is needed to confirm their diagnosis. The aim of the present work was to investigate of the extent of overlap between CAD and PAH in patients with SSc. METHODS: Based on non-invasive investigations, 20 patients out of 120 were suspected to have PAH ("suspected PAH" group). Another 10 patients showed signs of coronary disease ("suspected CAD" Group). In these 30 patients, right heart catheterisation and coronary angiography were performed, and the coronary flow reserve (CFR) was assessed by thermodilution technique. RESULTS: In the "suspected PAH" and the "suspected CAD" groups, PAH was found in 12/20 and 2/10 cases, and coronary artery stenosis in 9/20 and 6/10 cases, respectively. Severely reduced CFR was revealed in 7/20 and 3/10 cases, respectively. CONCLUSIONS: PAH, CAD and reduced CFR all show a considerable overlap in symptomatic patients with SSc. The current non-invasive investigations are neither sensitive nor specific enough to make an appropriate distinction between these different disease manifestations. A more invasive approach, such as coronary angiography at the initial catheterisation, is required to properly characterise and treat the different forms of cardiac involvement in SSc.

C1-inhibitor autoantibodies in SLE.

The presence of anti-C1-inhibitor (anti-C1-INH) autoantibodies is a hallmark of acquired C1-inhibitor deficiency. However, only scarce data are available on their prevalence, diagnostic value, and/or significance in systemic lupus erythematosus (SLE). In a multicentre study, we determined the levels of autoantibodies to C1-inhibitor in sera from 202 patients with SLE and 134 healthy controls. Additional clinical and laboratory parameters, such as organ involvement, as well as anti-C1q, anti-double-stranded DNA antibody, erythrocyte sedimentation rate, C-reactive protein, C3 and C4 serum complement levels have been studied in patients. The level of anti-C1-INH IgG was significantly higher (p = 0.034) in SLE patients, than in the controls. A high anti-C1-INH level of > or =0.4 U/ml (mean of controls + 2 SD) was found in 17% of the patients, but in only 4% of the controls (p = 0.0003). The SLEDAI score was significantly higher (p = 0.048) and the duration of SLE was significantly longer (p = 0.0004) among patients with elevated anti-C1-INH levels compared with patients without this autoantibody (median disease duration 8 vs. 17 years, respectively). Anti-C1-INH level was not correlated with any other laboratory parameter or organ manifestation of the disease. These findings indicate that the anti-C1-INH level is higher in SLE patients than in healthy controls and furthermore, the anti-C1-INH level correlates with the duration and activity of the disease.

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

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.

European League Against Rheumatism (EULAR) Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis: methods of elaboration and results of systematic literature research.

OBJECTIVE: To describe methods and procedures used for the development of the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis. In particular, the results of a web-based Delphi exercise aimed at selection of research questions and evidence from systematic literature research, as parts of the development of these recommendations, are presented in detail. METHODS: In agreement with the EULAR standard operating procedures a Task Force was created that consisted of the EUSTAR board members, 10 systemic sclerosis (SSc) experts invited from outside the EUSTAR board and representing Europe, the USA and Japan, a clinical epidemiologist, 2 patients with SSc and 3 fellows for literature research. All EUSTAR centres were invited to contribute to the development of recommendations through submission and preliminary selection of the research questions. The systematic literature research was performed using the Pubmed, Medline, EMBASE and Cochrane databases. Retrieved trials were evaluated according to the Jadad classification, and the level of evidence was graded from 1 to 4. Outcome data for efficacy and adverse events were abstracted and effect size, number needed to treat (NNT) and number needed to harm (NNH) were calculated when appropriate. RESULTS: In all, 65 EUSTAR Centres provided 304 research questions concerning SSc treatment. These questions were aggregated, subdivided into 19 treatment categories and then subjected to preliminary selection by a web-based Delphi technique. The final set of 26 research questions was created by the Expert Committee based on the results of the Delphi exercise and the expert's experience. CONCLUSIONS: This paper is a comprehensive summary of the methods we used to build recommendations for the drug treatment of systemic sclerosis, combining an evidence based approach and expert opinion.

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.

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 Raynaud's 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.

Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey.

BACKGROUND: A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). METHODS: DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. RESULTS: A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. CONCLUSIONS: For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. TRIAL REGISTRATION: Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).

Survival and causes of death in 366 Hungarian patients with systemic sclerosis.

OBJECTIVE: Survival analysis of a series of 366 consecutive patients with systemic sclerosis (SSc). METHODS: Clinical and laboratory data were evaluated from 1983 until 2005 using a standard protocol. The female/male ratio was 315/51. The mean (SD) age of the patients was 56.8 (12.2) years. The duration of disease was 12 (5-19) years with a median follow-up of 6 (3-12) years. RESULTS: Kaplan-Meier univariate analysis showed that renal, cardiac involvement, pigmentation disturbances, malabsorption, a forced vital capacity <50%, diffuse scleroderma, presence of early malignancy, anaemia, and increased erythrocyte sedimentation rate (ESR) were signs of unfavourable prognosis, whereas anti-centromere antibodies were indicators of a good survival. In the multivariate Cox proportional hazards model the presence of diffuse scleroderma, renal involvement, coexistence of a malignant disease, and increased ESR were poor independent prognostic signs. Elderly age at the onset of disease also caused an unfavourable outcome. A total of 86 SSc-related deaths were recorded during the follow-up. Of them, 65% were attributed to cardiorespiratory manifestation of disease. Tumour associated early death was found in 12 cases (14%). CONCLUSIONS: In addition to the well-known factors influencing the outcome (diffuse subset, internal organ involvements, and inflammatory signs), the coexistence of scleroderma with a malignancy also causes a poor outcome.

Functional variants of interleukin-23 receptor gene confer risk for rheumatoid arthritis but not for systemic sclerosis.

OBJECTIVES: Recently, an association was found between Crohn's disease and the interleukin-23 receptor (IL-23R) gene. Since the IL-23/IL-17 pathway is known to associate with other autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc), we hypothesised that IL-23R could be a shared susceptibility gene. METHODS: Groups of patients with rheumatoid arthritis (n = 412), systemic sclerosis (n = 224), Crohn's disease (n = 190) and healthy controls (n = 220) were genotyped for rs10889677 (exon-3'UTR C2370A), rs2201841, and rs1884444 variants; the first two have been shown to confer risk for Crohn's disease. RESULTS: We observed an increased prevalence of the homozygous rs10889677 AA and homozygous rs2201841 CC genotypes both in the Crohn's disease and in the RA groups as compared to the controls (12.1%, 11.9% vs 5.91%, p<0.05; and 13.2%, 13.1% vs 5.91%, p<0.05), but not in the SSc patients. Logistic regression analysis revealed that bearing these alleles represent risk for the development of rheumatoid arthritis (chi(2) = 5.58, p = 0.018, OR = 2.15, 95% CI 1.14-4.06 for rs10889677; and chi(2) = 7.45, p = 0.006, OR = 2.40, 95% CI 1.28-4.51 for rs2201841). The rs1884444 allele, which has been previously reported as neutral for development of Crohn's disease, was also found neutral for all studied groups in the present study. CONCLUSIONS: The data reported here provide direct evidence that some allelic variants or haplogroups of IL-23R represent independent risk factors for rheumatoid arthritis as well as Crohn's disease, but not for scleroderma.

Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: a European EUSTAR-initiated multi-centre case-control study.

OBJECTIVES: To determine the prevalence of anti-Ku antibodies in 625 patients with systemic sclerosis (SSc) from six European rheumatological centres and to evaluate their clinical and serological characteristics. METHODS: Sera of 625 consecutive patients with either limited cutaneous or diffuse cutaneous SSc were tested for antibodies to Ku antigen together with other extractable nuclear antigens by counterimmunoelectrophoresis. A case-control design with calculation of bootstrap 95% confidence intervals derived from anti-Ku negative control patients was used to evaluate clinical associations of anti-Ku antibodies. Sera from anti-Ku positive patients with SSc and a control group were additionally tested by immunofluorescence on Hep-2 cell substrates and line immunoassay. RESULTS: Anti-Ku antibodies were found in the sera of 14/625 (2.2%) patients with SSc. Of 14 anti-Ku positive patients with SSc, 10 had no other anti-extractable nuclear antigen (ENA) antibodies detected by counterimmunoelectrophoresis. Using a case-control study design, anti-Ku antibodies were significantly associated with musculoskeletal manifestations such as clinical markers of myositis, arthritis and joint contractures. In addition, a significant negative correlation of anti-Ku antibodies was found with vascular manifestation such as fingertip ulcers and teleangiectasias. There was a striking absence of anti-centromere antibodies as well as anti- polymyositis (PM)/scleroderma (Scl) antibodies in patients that were anti-Ku positive. As expected, anti-Scl70 and punctate nucleolar immunofluorescence patterns were present only in single cases. CONCLUSION: This is the largest cohort to date focusing on the prevalence of anti-Ku antibodies in patients with SSc. The case-control approach was able to demonstrate a clinically distinct subset of anti-Ku positive patients with SSc with only relative clinical differences in skeletal features. However, the notable exceptions were signs of myositis. This shows the importance of anti-Ku antibody detection for the prediction of this specific clinical subset.