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ObjectiveTo examine the outcomes of hand radiographic x-rays in patients with systemic sclerosis (SSc) and to identify risk factors for the progression of hand radiographic lesions in a prospective cohort.MethodsDual time-point x-rays were systematically performed after a median interval of 5 years (range 4–7 years) in 103 consecutively recruited patients with SSc. Univariate and multivariate Cox proportional hazards models evaluated predictors of progression of hand radiographic lesions.ResultsRadiographic progression of erosive arthritis, acro-osteolysis, calcinosis and flexion contracture occurred in 24, 22, 27 and 18 patients, respectively. Multivariate Cox regression analysis did not identify any predictor of the progression of erosive arthritis. Digital ulcers were shown independently to predict the progression of acro-osteolysis and calcinosis (HR 12.43, 95% CI 1.97 to 88.40 and 3.16, 95% CI 1.22% to 9.43%, respectively). The diffuse cutaneous subset was shown to be an independent predictor of the progression of flexion contracture (HR 7.52, 95% CI 1.21 to 43.93).ConclusionThe results highlight the striking level of hand radiographic lesions in SSc and suggest close monitoring of patients with the diffuse cutaneous subset for the occurrence or worsening of this complication. The results also show that severe peripheral vascular involvement predicts both acro-osteolysis and calcinosis, highlighting their vascular background.

Cardiac involvement, a common and often fatal complication of systemic sclerosis (SSc), is currently detected by standard echocardiography enhanced by tissue Doppler echocardiography (TDE).The performance of the biomarker of cardiovascular disease, N-terminal pro-brain natriuretic peptide (NT-proBNP), in the detection of cardiac involvement by SSc was examined.A total of 69 consecutive patients with SSc (mean (SD) age 56 (13) years, 56 women) were prospectively studied with standard echocardiography and TDE measurements of longitudinal mitral and tricuspid annular velocities. Plasma NT-proBNP was measured in all patients.Overall, 18 patients had manifestations of cardiac involvement, of whom 7 had depressed left ventricular and 8 depressed right ventricular myocardial contractility, and 8 had elevated systolic pulmonary arterial pressure. Patients with reduced contractility had increased mean (SD) NT-proBNP (704 (878) pg/ml versus 118 (112) pg/ml in patients with normal myocardial contractility, p0.001). Similarly, NT-proBNP was higher in patients with (607 (758) pg/ml) than in patients without (96 (78) pg/ml) manifestations of overall cardiac involvement (p0.001). Receiver operating characteristic analysis showed NT-proBNP reliably detected depressed myocardial contractility and overall cardiac involvement (area under the curve 0.905 (95% CI 0.814 to 0.996) and 0.935 (95% CI 0.871 to 0.996), respectively). Considering patients with SSc with normal echocardiography and TDE as controls, and using a 125 pg/ml cut-off concentration, sensitivity and specificity were 92% and 71% in the detection of depressed myocardial contractility, and 94% and 78% for overall cardiac involvement.NT-proBNP reliably detected the presence of cardiac involvement and appears to be a very useful marker to risk stratify patients presenting with SSc.

Background: Heterogeneous data have been reported regarding the detection and number of circulating endothelial progenitor cells (EPCs) in systemic sclerosis (SSc). Objective: We investigated the number of circulating EPCs using recent recommendations and we quantified their late outgrowth in patients with SSc and healthy controls. Patients and methods: EPCs, defined as Lin–/7AAD–/CD34+/CD133+/VEGFR-2+ cells, were quantified in 50 patients with SSc (mean age: 55 (16) years, disease duration: 9 (9) years) and 26 controls (mean age: 53 (19) years) by cell sorting/flow cytometry and by counting late outgrowth colony-forming units (CFU). Results: Patients with SSc displayed higher circulating EPC counts than controls (median 86 (5–282) vs 49 (5–275)) EPCs for 1 million Lin– mononuclear cells; p = 0.01). Lower EPC counts were associated with the higher Medsger’s severity score (p = 0.01) and with the presence of past and/or current digital ulcers (p = 0.026). There was no difference for the number of late outgrowth EPC-CFUs between patients with SSc and controls in cell culture evaluation. The formation of colonies was associated with higher levels of circulating EPCs (p = 0.02) and the number of colonies correlated with levels of EPCs (R = 0.73, p = 0.0004), validating our combination of fluorescence-activated cell sorter surface markers. Conclusions: We quantified circulating EPCs with an accurate combination of markers herein validated. Our data demonstrate increased circulating EPC levels in SSc, supporting their mobilisation from bone marrow. Furthermore, the subset of patients with digital vascular lesions and high severity score displayed low EPC counts, suggesting increased homing at this stage. The predictive value of this biomarker now warrants further evaluation.

Objective: To determine the effects of recently available oral therapies, ie, endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDEIs), in patients with pulmonary arterial hypertension related to connective tissue disease (CTD), mostly systemic sclerosis (SSc). Method: A systematic literature search was conducted up to April 2007. All randomised controlled trials evaluating the efficacy of bosentan, sitaxsentan and sildenafil vs placebo on exercise capacity were selected. Effect size was calculated in each study to assess the magnitude of treatment effect. Results: In all, 10 studies were analysed, giving a total of 613 participants (186 with CTD) who received the active treatment and 272 (72 with CTD) who received placebo. The effect sizes of bosentan, sitaxsentan and sildenafil for exercise capacity in the CTD subset of patients were non-significant; 0.31 (95% confidence interval (CI) −0.22 to 0.83), 0.26 (95% CI −0.06 to 0.57) and 0.53 (95% CI −0.02 to 0.89), respectively. In the whole PAH population, these values were significant; 0.61 (95% CI 0.38 to 0.84), 0.33 (95% CI 0.15 to 0.51) and 0.58 (95% CI 0.38 to 0.79), respectively. Conclusion: This meta-analysis suggests an absence of clinically relevant improvement on exercise capacity in patients with CTD/SSc after 12 to 18 weeks of treatment. A poor therapeutic response, insufficient power of studies or poor sensitivity to change of the 6-min walk test may explain these results. The promising preliminary data on survival of ERAs and the confounding effects of other comorbidities associated with CTD and SSc may support the latter hypothesis.

Objectives: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. Methods: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. Results: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. Conclusions: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Background: Cardiac involvement in idiopathic inflammatory myopathy has been recognised as an important prognostic factor, but treatment remains empirical. Objective: To investigate the effects of corticosteroids and immunosuppressors on myocarditis in patients with inflammatory myopathies. Methods: Patients with inflammatory myositis of recent onset who had not received treatment were evaluated for associated myocarditis by magnetic resonance imaging (MRI) and reinvestigated after treatment with high dose corticosteroids and immunosuppressors. Results: Four patients with histologically proven myositis were included. Two patients with polymyositis had cardiac clinical symptoms. Two other patients with dermatomyositis and diffuse cutaneous systemic sclerosis-polymyositis overlap syndrome were asymptomatic. In three cases the usual conventional screening tests were normal. For all patients an area of contrast enhancement and hypokinesia detected by cardiac MRI was markedly reduced after treatment with corticosteroids and immunosuppressors for 6 months. Conclusion: Treatment with intravenous methylprednisolone followed by prednisone and immunosuppressive therapy seems to be effective for treating myocardial involvement in patients with idiopathic inflammatory myopathies, either alone or presenting as overlap syndromes. Cardiovascular MRI is a non-invasive technique that may be a powerful tool for diagnosis and monitoring of myocardial inflammation in this setting.

Background: The osteoarticular and soft tissue structures of the hand may be involved in systemic sclerosis (SSc), causing functional disability. Objective: To assess radiological hand features in a cross sectional study of SSc patients and in controls. Methods: Hand radiology was done systematically in patients with SSc seen over a two year period and in unselected controls with rheumatoid arthritis or digital trauma. Two independent investigators blind to the diagnosis carried out the radiological assessment. Results: 120 consecutive SSc patients (median (range) age, 56.5 (20 to 90) years; disease duration, 6 (0 to 42) years) and 42 controls (22 with rheumatoid arthritis and 20 with digital trauma) were studied. Radiological abnormalities in SSc patients included erosion (21%), joint space narrowing (28%), arthritis (defined by concomitant erosion and joint space narrowing) (18%), radiological demineralisation (23%), acro-osteolysis (22%), flexion contracture (27%), and calcinosis (23%). In univariate and multivariate analysis, the resorption of distal phalanges was significantly associated with digital ulcers, extra-articular calcification, and pulmonary arterial hypertension; flexion contracture was associated with the diffuse cutaneous form and high HAQ (Health Assessment Questionnaire) disability score. Calcinosis was most often seen in patients with digital ulcers, but was similarly observed in patients with the diffuse or limited cutaneous subtypes. Conclusions: Flexion contracture was associated with disability and occurred in patients with the diffuse cutaneous subtype of SSc, consistent with the tendency towards fibrosis and functional impairment of this subtype. Calcinosis and acro-osteolysis were both associated with vascular complications, highlighting a potential role of vascular injury in such lesions.

Background: Primary myocardial involvement due to microcirculation impairment is common in systemic sclerosis (SSc). Cardiovascular magnetic resonance imaging (MRI) and tissue Doppler echocardiography (TDE) were recently shown to be more sensitive than conventional methods for the respective assessment of myocardial perfusion and contractility. Previous studies have suggested that dihydropyridine-type calcium channel blockers mitigate both myocardial perfusion and function abnormalities. Objective: To investigate the effects of nifedipine on myocardial perfusion by MRI and on contractility by TDE, in patients with SSc. Patients and methods: 18 patients with SSc without clinical heart failure and with normal pulmonary arterial pressure (14 women, 4 men; mean (SD) age 59 (9) years; mean (SD) disease duration 7 (4) years, 10 with diffuse and 8 with limited cutaneous forms) were prospectively evaluated. The MRI perfusion index, determined from time-intensity curves, and systolic and diastolic strain rate determined by TDE were assessed at baseline, after a 72 hour vasodilator washout period, and after 14 days of oral treatment with nifedipine 60 mg/day. Results: Nifedipine treatment led to a significant increase in the MRI perfusion index (mean (SD) 0.26 (0.07) v 0.19 (0.05) at baseline, p = 0.0003) and in systolic and diastolic strain rate (2.3 (0.6) v 1.5 (0.4) s −1 at baseline, p = 0.0002, and 4.2 (1.6) v 3.0 (1.2) at baseline, p = 0.0003, respectively). Conclusion: Fourteen days of treatment with nifedipine simultaneously improves myocardial perfusion and function, as evaluated by highly sensitive and quantitative methods.

The minor allele of the R620W missense single‐nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non‐receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo. Systemic sclerosis (SSc) is a connective tissue disease with some autoimmune abnormalities. The aim of our study was to test for association of the PTPN22*620W allele with SSc in a French Caucasian cohort with a case–control study of 121 patients with SSc and 103 controls. All patients and controls were genotyped for the PTPN22*R620W SNP. No association was found between the PTPN22*620W allele and SSc (7% v 9.2%, p = 0.39). The frequency of genotypes carrying at least one 620W allele was similar in both groups (13% v 17%, p = 0.38). The PTPN22*620W allele was also not associated with autoantibody patterns. Thus, the PTPN22*R620W polymorphism cannot be regarded as a genetic susceptibility factor for SSc in the French Caucasian population.

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.

Cardiovascular diseases, vasospasm, and dysimmunity have been implicated in normal tension glaucoma (NTG).To investigate the prevalence of ocular abnormalities suggestive of glaucoma damage in systemic sclerosis (SSc).61 patients with SSc (mean (SD) age 56.2 (12) years, mean (SD) disease duration 9.9 (9) years; 41 with limited cutaneous disease) and 37 control subjects with osteoarthritis (mean (SD) age 55.9 (12) years) were studied. They were systematically referred to an ophthalmologist. The evaluation was based on aplanation tonometry, ophthalmoscopy with retinal photography (evaluation of cup/disc ratio (c/d)), and automated static perimetry (determination of mean defects (MD)). Statistical analyses were performed with the chi(2), Mann-Whitney, and Spearman tests.The mean visual acuity and intraocular pressure were similar in both groups. An excavation with a c/d0.3 was found in 27 eyes from patients with SSc and 5 eyes from controls (p = 0.009); a c/d0.7 was found in 4 eyes from patients with SSc and none in the controls (NS). Visual field defects (MD-2 dB) were found in 55 eyes from patients with SSc and in 18 eyes from controls (p0.0001). A concomitant c/d0.3 and MD-2 dB was found in 21 eyes from 12 patients with SSc but in none of the control eyes (p0.0001).Ocular abnormalities suggesting glaucomatous neuropathy without ocular hypertension were dramatically more prevalent in patients with SSc. These abnormalities seem to be mild but justify long term follow up. They are consistent with the vascular pathogenic hypothesis for NTG.

Background Cutaneous telangiectasia (CT) are visible macular dilated superficial blood vessels. CT are an item of the new 2013 ACR/EULAR classification criteria for systemic sclerosis (SSc) (1) and are part of the newly established detection algorithm for SSc-related pulmonary arterial hypertension (2). These recent achievements highlight the importance of CT both for the diagnosis and prognosis of the disease. The number and size of CT can strongly vary from a patient to another according to the severity and progression of SSc-related vasculopathy. Nailfold videocapillaroscopy (NVC) is an accurate tool to evaluate microangiopathy allowing to discriminate vascular disease activity. Objectives The aim of our study was to determine whether the number and size of CT were associated with specific NVC features. Methods We performed a cross-sectional study including consecutive SSc patients over a 9-month period. We considered three subset of patients according to the number of hand or face CT: absence of CT, ≤10 hand or face CT (minor to moderate CT) or >10 CT (profuse CT). Pseudotumoral CT were also taken into account and were defined as CT with >5mm diameter. NVC was performed and classified as early, active and late patterns (3). Results 87 patients were included (69 females), with a median age of 58 years (range 19-89 years), and a median disease duration of 11 years (range 0-53 years). 75 patients (86%) had CT: 27 (36%) had profuse CT, and 19 (25%) pseudotumoral CT. In univariate analysis, patients with profuse and pseudotumoral CT were more likely to have the late NVC pattern (p=0.003 and p=0.001 respectively). Profuse and pseudotumoral CT were also associated with capillary loss (5.09±1.25 vs. 7.73±2.1 capillaries/digit, p 14 ng/L) (p In multivariate logistic regression analysis, we confirmed that pseudotumoral CT were independently associated with the late NVC pattern (odds ratio, OR: 5.22, 95% confidence interval, CI, 1.09-29.95, p=0.038) and especially with neoangiogenesis (OR: 7.77, 95% CI 1.30-46.36). Conclusions Our study reveals an independent association between pseudotumoral CT and the late NVC pattern. Our findings also show a relationship between pseudotumoral CT and neoangiogenesis, both characterized by ramified and bushy capillaries. These results support the development of a more accurate classification and staging of CT. This simple clinical finding might improve risk stratification of the vascular risk of SSc patients. References Van den Hoogen et al, Ann Rheum Dis 2013 Coghlan et al, Ann Rheum Dis 2014 Cutolo et al, J Rheumatol 2000 Disclosure of Interest None declared

Background Microangiopathy is a cardinal feature of systemic sclerosis (SSc), which plays a critical role in the development of primary myocardial involvement and pulmonary hypertension, two major causes of death in SSc. Objectives Our aim was to measure plasma concentrations of two cardiac biomarkers, high sensitive Cardiac troponin T (HS-cTnT), a marker of myocyte necrosis and/or ischemia, and N-terminal fragment of pro-BNP (NT-proBNP), a marker of cardiac strain, in two large cohorts of SSc patients and controls. Methods 161 SSc patients (135 women, 84%) with a mean ± SD age of 57±17 years were included and were compared to 213 healthy controls (170 women, 80%, mean ± SD age of 55±11 years). The plasma HS-cTnT concentrations were measured using an electrochemiluminescence immunoassay (Roche Diagnostic, Meylan, France). The 99th percentile, with a CV ≤10% was achieved for 14 ng/L. Plasma NT-proBNP levels were assessed by an immunoenzymatic assay (Roche Diagnostic). Results Among the SSc cohort, mean disease duration was 9±8 years, 65 patients (40%) had the diffuse cutaneous subset. HS-cTnT and NT-proBNP plasma levels were significantly increased in SSc patients versus controls (p=0.0001 and p 14 ng/L) and NT-proBNP than controls (30/161 patients (19%) with HS-cTnT >14 ng/l vs. 4/213 controls (2%), p Multivariate logistic regression analysis confirmed diabetes mellitus (p=0.006), high blood pressure (p=0.02), precapillary pulmonary hypertension (PH) (p=0.04), ESR >28 mm/H1 (p=0.007) and the diffuse cutaneous subset (p=0.004) as factors independently associated with HS-cTnT >14 ng/L. Increased NT-proBNP concentrations were only associated with the presence of precapillary PH (p=0.0001). The combination of increased HS-cTNT and NT-proBNP levels had the highest positive predictive value for the diagnosis of precapillary PH (67%) compared to HS-cTnT (20%) or NT-proBNP (35%) alone. Conclusions Plasma levels of HS-cTnT and NT-proBNP are increased in SSc patients. Associated factors with increased HS-cTnT include the diffuse cutaneous subset and precapillary PH, which reflect the severity of the disease. In addition, the combination of increased HS-cTnT and NT-proBNP plasma concentrations display higher positive predictive value for the diagnosis of precapillary PH than each marker alone. Given the prognostic significance of these biomarkers, they might be helpful to select the patients that justify further examinations in case of suspicion of cardiac complication. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4011

Background Vitamin D plays an important role in the modulation of immune system and epidemiologic data indicate low vitamin D levels in autoimmune diseases such as rheumatoid arthritis (RA), connective tissue disorders, inflammatory bowel diseases and multiple sclerosis. Several studies reported contradictory results regarding correlation between disease activity and vitamin D levels in these diseases. Objectives To assess 25-OH vitamin D concentrations in 2 independent cohorts of patients affected by inflammatory rheumatic disorders (IRD) and correlations with disease activity and disability. Methods We retrospectively analyzed 420 patients (246 RA, 100 ankylosing spondylitis (SA), 74 psoriatic arthritis (PsA) followed at Rheumatology tertiary centers in Northern France (Paris) and Southern Italy (Cagliari). All patients underwent clinical and laboratory evaluation including serum calcium and phosphorus levels, 25-OH vitamin D and parathyroid hormone (PTH). Vitamin D concentrations Results Vitamin D insufficiency and deficiency was very high: respectively 66% and 19% in RA, 76% and 10% in AS, 83% and11% in PsA. Their incidence was comparable between the two populations in RA (68% and 20% versus 62% and 18%, P = ns, respectively in the French and Italian patients), while it was significantly higher among French compared to Italian patients in AS and PsA (86% and 23% versus 61% and 0, P=0.005 and P=0.002; 89% and 20% versus 55% and 3%, P=0.002 and P=0.02, respectively in AS and PsA). Vitamin D supplementation was statistically different only in RA patients (53% versus 34%, P=0.003, respectively in French and Italian patients). In the combined populations, in RA patients, no correlation was observed between vit D and DAS score but treated patients with anti-TNF alpha agents had higher vitamin D levels (P=0.01). In SA patients low vitamin D concentrations correlated with higher BASFI (R = -0,02; P Conclusions A high incidence of vitamin D deficiency was found in IRD in the two populations, independently of geographic origin for RA, while a higher incidence was seen in French AS and PsA patients, suggesting a potential different influence of vitamin D on these diseases. By contrast, no correlations with disease activity were found except for disability index BASFI in AS patients. In our study, TNF alpha agents seem to improve vitamin D levels as well as disease activity, but it remains controversial if this is an effect linked to disease activity modulation or it directly depends from immunomodulatory properties of vitamin D. This finding encourage to perform randomized controlled studies for confirming that vitamin D supplementation could reduce the risk of autoimmunity or that it eases disease activity, although there is still not a clear consensus about the optimal circulating 25-OH vitamin D levels and the supplementation dosage for maintaining immune homeostasis. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5038

Background TNF-a inhibitors have completely changed the prognosis of rheumatoid arthritis (RA). The number of molecules and the time of exposure have increased. However, few studies have compared i) the safety of the five now available TNF-a inhibitors between them, and ii) their medium term safety (after more than 6 months of use). Objectives The aim of our study was to compare the data regarding medium-term safety obtained from randomized controlled trials for the five TNF-a inhibitors used in the treatment of RA. We particularly aimed to focus on two serious events: death and severe infections. Methods A systematic review of articles published from January 2000 to January 2013 was performed using MEDLINE, EMBASE and COCHRANE databases. We included randomized, controlled, double blind and parallel-group trials, with a follow-up period of at least 6 months, comparing TNF-a inhibitors to placebo, with or without concomitant treatment with Methotrexate. The primary outcome measure was the occurrence of a serious adverse event, defined by the occurrence of death or of a serious infection (this latter defined in all studies by the requirement of hospitalization). Secondary outcome measures were the occurrence of death or serious infection. MedCalc software was used for the statistical analysis. Results Among the 396 articles initially identified, 22 were finally selected. These articles included 6682 patients in the TNF-a inhibitor group (Adalimumab: 2507, Golimumab: 575, Certolizumab: 1512, Infliximab: 1087 and Etanercept: 1001) and 3607 in the placebo group. The duration of patient follow-up ranged from 24 to 78 weeks. The analysis of our primary outcome showed no increased risk of serious adverse event (death or severe infection) in the TNF-a inhibitor group compared to the placebo group (Odds Ratio, OR: 1.14, 95% Confidence Interval, CI: 0.91-1.44). Sensitivity analysis with respect to each molecule did not change the main conclusion, except for Certolizumab, which showed an increased risk of serious adverse events (OR: 2.06, CI: 1.35-3.15). Regarding secondary outcomes, no increased risk of death in the TNF-a inhibitor group compared to the placebo group was observed (OR: 1.27, CI: 0.71-2.25). However, increased risk of severe infections in the TNF-a inhibitor group was observed compared to the placebo group (OR: 1.66, CI: 1.25-2.23). Sensibility analysis with respect to each molecule did not change the main conclusion regarding the risk of death, but revealed that adalimumab had an increased risk of severe infection (OR: 2.10, CI: 1.28-3.46). Conclusions This meta-analysis has been performed on a large number of patients and included the five TNF-a inhibitors currently available. It allowed an indirect comparison between the different molecules according to their medium-term safety. We did not find an increased risk of serious adverse events or deaths in patients treated with TNF-a inhibitors. However, we observed an increased risk of severe infections. Further studies aiming at the evaluation of the long-term safety are now needed to confirm these results. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3230

Background Few studies focused on the course of biotherapies in juvenile idiopathic arthritis (JIA). Results of these studies showed that anti-TNFalpha drug survival was comparable to adult rheumatoid arthritis. However, these JIA studies had short follow-up and focused only on anti-TNFalpha drug. Objectives Determine the course of biotherapies and the risk factors for discontinuation in a large cohort of JIA at adulthood. Methods A retrospective observational study of the use of biotherapies has been conducted in a large monocentric cohort of JIA patients at adulthood fulfilling ILAR criteria. Following data were collected: biotherapies treatments (Etanercept, Adalimumab, Abatacept, Tocilizumab and off label Infliximab, Anakinra and Rituximab), causes of discontinuation (adverse events, primary inefficacy, secondary inefficacy and inactive disease), age at diagnosis, uveitis, inflammatory bowel disease (IBD), psoriasis, presence of radiographic damages, coxitis, history of surgery, presence of antinuclear antibodies, rheumatoid factors, anti-CCP, and finally concomitant treatments of the biotherapy by corticosteroids or DMARDs. Results 106 patients with JIA persisting at adulthood were included with a mean age of 22.5±9.7 years and a mean disease duration of 13.3±6.4 years. The mean follow-up since the start of biological treatment was 6.7±3.6 years and the mean number of biotherapies per patient was 2.2 [1-7]. 49/106 (52%) patients needed only one biotherapy during all the course of their disease. Among these 49 patients, 43 (88%) patients remained on their first-line of biotherapy during all the course of the follow-up and only 6 (12%) could stop definitively their biotherapy. Reasons for changing the first to the second line of biological treatment (n=57) were side effects (n=12), primary inefficacy (n=12), secondary inefficacy (n=22) and inactive disease (n=6) an others (n=5). The mean duration of the first biological treatment was 44.5±41.4 [2-158] months, for the second biotherapy 28.8±28.4 [1-93] months and for the third biotherapy 15.5±15.8 [1-54] months. The duration of the first biological treatment was not influenced by the concomitant use of DMARDs or corticosteroids but the use of this latter was strongly associated with the risk to need switching from the first to a second line of biological treatment (81% vs 51%, p=0.001). The risk factor for discontinuation of the first biological treatment was the presence of radiographic damages (p=0.04, OR=2.3 [1-5.2]). There was also a tendency for a lower age at diagnosis (p=0.08) and the systemic form of JIA (p=0.07) in JIA patients needing more than one biotherapy. No association was detected for sex, uveitis, IBD, psoriasis, antibodies status and surgery. Conclusions In this large cohort of JIA patients at adulthood, more than half of patients remained on their first line of biological treatment after more than 6 years of treatment. The main risk factors for discontinuing the first biotherapy were inefficacy (primary or secondary) in 60% and as expected the percentage increased with the lines of treatments. Associated factor with the use of more than one biotherapy was an erosive form of JIA. Concomitant use of corticosteroids was associated with drug survival. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5215

Background Calcinosis and acro-osteolysis are frequent in systemic sclerosis (SSc) and are easily detected by X-rays (1). Recent findings indicate that these lesions may be related to digital vasculopathy. Accumulating evidence support the input of nailfold videocapillaroscopy (NVC) as a marker of digital vasculopathy. Objectives To determine whether calcinosis and acro-osteolysis are associated with specific NVC features. Methods Consecutive SSc patients were consecutively included during a 24-month period. NVC was performed and analysed by one investigator (JA) blinded for the results of X-Rays and classified as early, active and late pattern (2). Two independent investigators carried out radiological assessment on standard anteroposterior views of the hands and wrists (LM, MS), followed by a consensus reading (AF and YA). Calcinosis was defined by the presence of at least one calcification in soft tissue and acro-osteolysis by the presence of the resorption of at least one digit tip. Both were classified on X-rays as mild, moderate or severe according to their extent. Results 155 patients were included, with a mean age of 57±13 years and a mean disease duration of 9±5 years; 65 (42%) had the diffuse cutaneous subset. 15 (10%) patients had a normal, 46 (30%) an early, 47 (30%) an active, and 47 (30%) a late NVC pattern. Regarding X-ray analysis, the kappa coefficient of inter-rater agreement was 0.75. 43 (28%) patients had calcinosis, of whom 26 (17%) had moderate or severe lesions; 25 (16%) patients had acro-osteolysis; of whom 13 (8%) had severe lesions. Patients with calcinosis were more likely to have acro-osteolysis (p=0.02), but Cramer9s V coefficient of association was 0.19, supporting low association between these variables. Patients with calcinosis and acro-osteolysis were more likely to have the late NVC pattern (p=0.04 and p 14 (p=0008) and positive antitopoisomerase-I antibodies (p=0.01). Conclusions We show for the first time an independent association between calcinosis/acro-osteolysis and the late NVC pattern, and in particular, with reduced number of capillaries. This result suggests that these lesions may be related to the severe capillary loss observed at this stage. Acro-osteolysis, but not calcinosis, was associated with neoangiogenesis, which may suggest an attempt to compensate bone resorption. Further studies are now needed to determine whether capillaroscopy may predict the further occurrence or worsening of these lesions. References Avouac J et al, Ann Rheum Dis 2006; (2) Cutolo M et al. J Rheumatol. 2000 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4427

Several cases of fatal exacerbations of fibrosing alveolitis associated with rheumatoid arthritis after infliximab treatment have recently been reported.1 We report here a case of fatal exacerbation of pulmonary fibrosis after adalimumab treatment in a patient with polyarthritis related to systemic sclerosis (SSc). The patient, a 74 year old woman, had been diagnosed 5 years previously with severe Raynaud’s syndrome, sclerodactyly, pulmonary fibrosis, abnormal oesophageal peristalsis, and non-specific antinuclear antibodies (1/100; indirect immunofluorescence on Hep 2 cells). She also had severe distal polyarthritis affecting the wrists, metacarpophalangeal and proximal interphalangeal joints, with demineralisation but no erosion on x ray examination. She tested negative for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Successive treatments with low dose prednisone associated with methotrexate, leflunomide or azathioprine were ineffective. In February 2004 she had a 28 joint count Disease Activity Score (DAS28) score of 7.8, a …

Background Gastro-Intestinal (GI) involvement is a well-known complication of Systemic Sclerosis (SSc). Small intestinal bacterial overgrowth (SIBO) is part of such involvement. It can compromise the patient quality of life and lead to severe outcomes (cachexia, high infectious risk). However, the prevalence of SIBO is not established and predictors remain unexplored. Objectives To estimate the prevalence of SIBO in patients with SSc exhibiting GI symptoms and identify subsets of patients at risk of SIBO regarding clinical and biological presentations and GI symptoms measured by standardised questionnaires. Methods Between 2011 and 2012, patients with SSc exhibiting GI complaints (pain, diarrhoea, bloating) underwent glucose hydrogen/methane breath tests (BT) and blood assays (CRP, ferritin, vitamins D, B9 and B12, albumin, calcium, phosphate, prothrombin and lipid profile). At the time of the BT, patients were asked to complete two questionnaires: the Short Form-36 (SF-36) and the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA SCTC GTI).1 Results Among 120 consecutive SSc patients, 38 patients (30 women) were included, (median age: 59 years (30-80)). Fourteen patients (37%) had a positive BT and were diagnosed with SIBO giving a point prevalence of 12% (14/120) in SSc and 37% (14/38) in SSc patients with GI symptoms. Among the 38 patients included, 18 (48%) had the diffuse cutaneous subset. Median disease duration was 8.5 years (1-35). Patients with SIBO showed a longer disease duration (13.5 years (4-29) vs. 6.5 (1-35), p=0.007); a higher frequency of pulmonary arterial hypertension confirmed by right heart catheterization (3/14, 21% vs. 0/24, 0%, p=0.01) and a lower frequency of anti-topoisomerase-I antibodies (1/14, 7% vs. 10/24, 42%, p=0.04). Median age (60.5 vs. 59 years, p=0.5) and cutaneous subset (36% vs. 54% patients with the diffuse form, p=0.5) did not differ between patients with or without SIBO. Of the most interest, significant weight-loss within the past 6 months (>5% of total body weight) was observed in patients with BT+ (6/14, 43% vs. 2/24, 8%, p=0.03). Despite normal median values, calcium (p=0.04), phosphate (p=0.04) and triglycerid levels (p=0.04) were lower in patients with SIBO. Focusing on GI manifestations, it is of note that the total UCLA SCTC GTI score was higher in patients suffering from SIBO (0.85 (0.24-2.22) vs. 0.30 (0.04-1.24), p=0.02). The SF-36 assessment was comparable between the 2 groups. Two patients died due to intestinal involvement with severe chronic malabsorption. Conclusions In our series, the prevalence of SIBO was 37% of SSc patients displaying GI symptoms. To our knowledge, this is the first study using the UCLA SCTC GTI to identify patients at risk of SIBO in SSc. Higher UCLA SCTC GTI score and weight-loss appeared to be strongly associated with SIBO. These results support the systematic use of this score, together with a regular weight evaluation in SSc patients. Further studies are needed to confirm these results on a larger scale and to assess the evolution of the UCLA SCTC GTI score after SIBO optimal treatment, which is currently ongoing in our unit. References Khanna D, et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum 2009; 61: 1257-63. Disclosure of Interest None Declared

Background Oxidative damage caused by oxygen free radicals is generally considered a serious mechanism in the pathogenesis of many diseases as cardiovascular diseases, atherosclerosis, and inflammatory rheumatism. Increased oxidative stress has already been described in plasma, saliva and articular fluid of juvenile idiopathic arthritis (JIA) patients. However, most of previous studies did not differentiate ILAR sub-types of JIA and were performed before era of biotherapies. Objectives Our aim was to determine characteristics of blood markers of oxidative stress in a large cohort of JIA at transitional period. Methods One hundred and ten consecutive JIA, fulfilling ILAR criteria, followed in a transition program were included. Age, sex, disease duration, medical or surgical treatments and remission status were collected. Following laboratory tests were performed: ESR, CRP systematically and antinuclear antibodies, rheumatoid factors and anti-CCP when required for the JIA diagnosis. Oxidative stress parameters were: AOPP (Advanced Oxidation Protein Products) and thiols proteins. Control group consisted of twenty healthy controls without inflammatory condition. Results Among the 110 patients’ cohort, there were 25 ERA, 16 persistent oligoarthritis, 19 extensive oligoarthritis, 18 polyarticular RF- and 18 RF+ and 14 systemic JIA. Mean age was 21±4 years and mean disease duration was 12.3±3.9 years. Mean global JIA dosage of AOPP was 56.4±47.5µmol/l and thiols proteins was 473.4±41.6µmol/l. No differences were detected when comparing JIA to controls for AOPP and thiols (p=0.4 and p=0.5, respectively). But, AOPP levels in extensive oligoarthritis sub-group was significantly higher than in controls group (82.6±52.9 vs 46.5±6.5, p=0.006). Comparison of oxidative stress parameters according to sub-types of JIA showed that extensive oligoarticular sub-groups was associated with higher degree of oxidative stress i.e. higher levels of AOPP compared to ERA and polyarticular JIA and lower levels of thiols proteins compared to ERA. Thiols proteins levels were strongly associated with disease activity parameters [remission status (p=0.008), number of synovitis (p=0.005), ESR level (p=0.008) and CRP level (p=0.0001)]. Conclusions Oxidative stress, in this large cohort of JIA patients at transitional period, is tightly associated with disease activity. This confirms that, in JIA, inflammation could lead to articular and/or profound organs damages by oxidative stress. An absolute tight control of JIA activity seems to be primordial for the future (cardiovascular, atherosclerosis) health of the JIA patients. Our results highlight the potential particularity of extensive oligoarticular sub-type of JIA concerning the oxidative stress. Disclosure of Interest None Declared

Objectives To investigate whether women with SSc have increased risk of OP and fractures compared to a “high risk” population with rheumatoid arthritis (RA) and also healthy controls. Methods Cross-sectional study with successive inclusion of age-matched healthy, SSc, and RA women on a 18-month period. Risk factors for OP and fractures, including age, menopausal status, calcium/vitamin D intake, family history, comorbidity and steroid use, were collected for all patients. Bone mineral density (BMD) was assessed at AP lumbar spine (L1-L4), femoral neck, and total hip region with DXA Prodigy (GE-Lunar) or QDR4500 (Hologic). We included 71 women with SSc (62±12 years old), 139 with RA (61±11 years old) and 227 healthy controls (60±8 years old). The mean ± standard deviation, SD, disease duration of SSc and RA patients was 10±9 and 18±13 years respectively (p vs. 19392±19333 mg, p vs. 7±7.9 mg/l, p=0.01). Results The point prevalence of OP (T-score vs. SSc and RA). The frequency of lumbar spine and total hip OP did not differ between SSc and RA. The point prevalence of fractures was 35% and 33% in SSc and RA, respectively (p=NS) and 10% in healthy controls (p vs. SSc and RA). The frequency of vertebral (25% and 19%) and non-vertebral fracture (23% and 22%) did not differ between SSc and RA. Multivariate analysis identified disease duration as the only risk factor of OP in SSc (odds ratio, OR: 1.21, 95% confidence interval, CI: 1.02-1.30). There was no association between OP and corticosteroid intake, cumulative dose of corticosteroids, systemic inflammation (CRP >10mg/l) or any SSc feature Age (OR: 1.21, 95% CI 1.03-1.38) and low 25(OH)D levels (OR: 6.02, 95% CI 1.46-24.78) were recognized as risk factors of fracture in SSc. In comparison, age (OR: 1.12, 95% CI 1.02-1.26) and corticosteroid treatment (OR: 3.21, 95% CI: 1.12-10.44) were independently associated with OP in RA. Cumulative dose of corticosteroids negatively correlated with BMD measured at lumbar spine (r=0.38, p=0.01) and total hip (r=0.49, p=0.008) in RA patients. Multivariate analysis confirmed age (OR: 1.09, 95% CI 1.03-1.18), OP (OR: 3.22, 95% CI 1.18-8.75) and low 25(OH)D levels (OR: 4.31, 95% CI 1.29-14.41) as independent risk factors of fractures in RA. Conclusions The prevalence of OP and fracture in SSc was increased compared to healthy women and reached the high prevalence associated with RA. Age and vitamin D deficiency were identified as risk factors of fracture in SSc. Thus, increasing the awareness and performance of BMD measurements together with vitamin D supply in patients with SSc is warranted. Disclosure of Interest None Declared

Background Health Related Quality of Life (HRQoL) is affected in Juvenile idiopathic arthritis (JIA) because of pain, functional impairment and joint destruction. The main quality of life score used in JIA is the C-HAQ (Child Health Assessment Questionnary), pediatric version of HAQ (Health Assessment Questionnary) used for adult. Transition of care includes a transfer from paediatric to adult health care. No previous specific evaluation of HRQoL had already been performed in this particular transitional period. Objectives In our study, we propose to determine the impact of JIA on QOL in a large transition JIA cohort and to evaluate which HRQoL questionnaire should be used in practice. Methods All consecutive patients with AJI followed during adulthood in a transition care program at Cochin Hospital were included. Demographics, clinicals and biologicals datas have been collected: tenderness and swelling joints (respectively TJS, SJS), decrease of joint mobility (LOM), visual analigic scale (VAS) of pain, activity and physician, erythrocyte sediment rate (ESR), CRP and currently therapy. Quality of life questionnary given were: CHAQ child and parent versions, HAQ, SF-36 and EuroQol. Results 121 JIA were included (82 women and 29 men). The mean age was 19.9±3.7 years [8-34]. The mean age at the diagnosis was 8.6±5.2. The mean age at the first symptom was 8.4±5 years [1-20] while the diagnosis was made nearly 28 months later. Sub-types of JIA were as followed: 44 oligoarthritis, 28 ERA, 5 psoriasic arthritis, 27 polyarticular form and 17 with systemic JIA. 58/121 (48%) are treated by biotherapy and 43/121 (36%) were considered in remission. CHAQ child and parents were respectively 0.6±0.6 and 0.6±0.7. The mean HAQ was 0.5±0.6. There is a strong correlation between CHAQ and HAQ (r=0.93, p Conclusions Evaluation of HRQoL in a large transition cohort of JIA patients at adulthood showed that JIA has a moderate impact on quality of life. JIA has more physical consequences compared to mental status of patients. His functional consequence could be evaluated by either HAQ or CHAQ but HAQ seems to be simpler and age-appropriate in practice. Mental status is evaluated in the same way by SF-36 or EuroQOL allowing the use of one or the other indifferently. Disclosure of Interest None Declared

Background Radiographic damage was recently considered to be a feature of poor prognosis in cases of polyarticular juvenile idiopathic arthritis (pJIA). However, most radiographic studies did not differentiate pJIA from other subtypes of JIA and did not include a control group. Furthermore little is known about radiographic damages in pJIA persisting into adulthood. Objectives To describe structural peripheral involvement in pJIA persisting into adulthood and compare observed lesions to those seen in rheumatoid arthritis (RA) using a cross-sectional observational study. Methods All consecutive pJIA followed in a transition program were included. Age, sex, disease duration, medical or surgical treatments were collected. Laboratory tests (ESR, CRP, Rheumatoid Factor (RF) and anti-CCP) and standard radiographies of the hands and wrists, feet and hip were performed. A RA control group ( Results 58pJIA (48 females/10 males) and 59 RA (52/7) were included. Respectively, mean age was 23.5±10.0 years and 43.2±9.6 years and mean disease duration 13.1±11.1 and 12.2±7.1 years. 60% and 80% were RF positive and 57% and 78% were anti-CCP positive (p=0.02). The inter-observer concordance coefficient kappa was 0.614 between the two investigators. Four pJIA patients had previous hand or feet surgery and 7 in RA group avoiding radiographs evaluation. Radiographs showed hand lesions in 41/54 (76%) pJIA and 42/50 (84%) RA-patients, feet lesions in 35/54 (65%) pJIA and 45/57 (79%) RA-patients and coxitis in 16/54 (30%) pJIA and 8/47 (17%) RA-patients (p=NS for all comparisons). Mean hands and feet scores were 17.9±21.8 and 7.7±10.8 in pJIA and 18.5±17.6 and 9.9±11.3 in RA, respectively (p=NS). Coxitis was bilateral in 13/16 (81%) in pJIA and in 2/8 (25%) of the cases of RA-patients, respectively (p=0.005). Hand damages involved wrists, metacarpophalangeal, proximal interphalangeal and distal interphalangeal joints in pJIA without statistical significant difference when compared to RA. RF-positive patients differed from RF-negative patients only by a shorter disease duration (10.4±9.3 vs. 17.3±12.6, p=0.02). Radiographic comparison between RF-positive and RF-negative patients revealed a higher frequency of hand damage (29/34 vs. 12/21) and less coxitis (5/31 vs. 11/23) in RF-positive subgroup (p=0.02 and 0.01, respectively). In pJIA, presence of radiographic damage correlated with a more severe disease phenotype: higher frequencies of biotherapies and surgery (p=0.009 and p=0.02, respectively), but not with RF status. Conclusions Structural peripheral damages are frequent in young adults with pJIA and correlated with a more severe disease. A specific feature to pJIA seems to be a high risk of bilateral coxitis. This requires a particular following and monitoring of pJIA patients with unilateral hip involvement to prevent bilateralization. Disclosure of Interest None Declared

The results and interpretation of the meta-analysis by Wandel and colleagues of the effects of glucosamine and chondroitin on osteoarthritis depend on the trials analysed and the thresholds defined as clinically relevant.1 The criteria for the selection of trials is questionable; the European Medicines Agency recommends evaluating the analgesic effect of slow acting drugs for osteoarthritis after at least six months of treatment, and the structural effect after two years. …

Ephrins have emerged as essential regulators of angiogenesis and thrombospondins are inhibitors of angiogenesis and strong promoters of fibrosis that are both involved in systemic sclerosis (SSc). Our aim was to analyse the expression of ephrins and thrombospondins concomitant to VEGF pathway assessment in skin specimens and dermal cultured fibroblasts from patients with SSc. Skin biopsies were obtained from 8 patients with early diffuse cutaneous subset. In all patients, biopsies were taken from both clinically involved and non-involved skin. Controls …

Infection with human parvovirus B19 causes a wide range of clinical manifestations, which may vary according to the immune status of the patient. They include erythema infectiosum (fifth disease), symmetrical polyarthritis, vasculitis, transient aplastic crisis in patients with low red cell production, and chronic infection in immunocompromised patients. We report a patient treated with immunosuppressive drugs in whom bilateral brachial plexitis and polyarthritis were associated with parvovirus B19 acute infection. A 33 year old woman presented with severe pain in the arms. She had a two year history of severe Crohn’s disease and was treated with azathioprine (125 …

The efficacy of diltiazem in the treatment of Raynaud's phenomenon was assessed in a prospective double-blind randomised cross-over trial in 16 patients (7 progressive systemic sclerosis, 2 rheumatoid arthritis, 1 systemic lupus erythematosus, and 6 idiopathic Raynaud's phenomenon). Each patient received diltiazem 120 mg and placebo three times a day for two weeks. The attack frequency of Raynaud's phenomenon was measured by a diary count; its severity was assessed by means of a 10 cm visual analogue scale with 0 representing minimum and 10 representing maximum severity. Diltiazem significantly decreased the frequency and severity of Raynaud's phenomenon as compared with placebo. This improvement was striking in patients with idiopathic Raynaud's phenomenon but did not reach statistical significance in patients with associated systemic disease. We conclude that diltiazem is effective in the treatment of Raynaud's phenomenon, especially in patients with idiopathic vasospastic disease.

We evaluated the effect of dipyridamole on thallium-201 myocardial perfusion in 23 patients with progressive systemic sclerosis (PSS) with diffuse scleroderma. Thallium-201 single photon emission computed tomography (SPECT) was performed at rest and after coronary artery vasodilatation with intravenous dipyridamole (0.14 mg/kg/min for four minutes). The left myocardium was divided into nine segments; each segment was graded as 2.0, 1.5, 1.0, 0.5, 0 (zero represents no activity). Dipyridamole significantly improved resting thallium-201 myocardial perfusion: the mean (SD) number of segments with thallium defects decreased from 6.0 (2.1) at rest to 4.1 (2.5) after dipyridamole (p less than 0.0001); the mean (SD) score in segments with resting defects increased from 0.92 (0.24) at rest to 1.13 (0.38) after dipyridamole (p less than 0.0001); the mean (SD) global score per patient increased from 10.2 (1.8) at rest to 11.4 (2.1) after dipyridamole (p less than 0.02); the global score increased by at least 2.0 in 12 patients and worsened by at least 2.0 in three patients only (p = 0.05). The results of this acute study suggest that some drugs with potent vasodilator activity on small coronary arteries may be beneficial in the treatment of PSS patients with thallium-201 myocardial perfusion abnormalities.