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Background:The patient global assessment (PGA) is the most widely used patient-reported measure in rheumatoid arthritis (RA), being a component of disease activity scores and definitions of remission. Studies have however shown that, at least in established RA, PGA is mostly associated with pain, functional limitation, psychological distress and comorbidities, rather than with objective measures of inflammation. As such, the inclusion of PGA as a driver of intensification of immunosuppressive therapy is been questioned. Determinants of PGA may however differ in the earliest stages of RA, when pain processing mechanisms and damage accrual have not occurred yet. Whether the association of PGA with disease activity in RA changes over time is at present undetermined.Objectives:To analyze the associations between PGA and disease activity measures in patients with RA across different phases of the disease.Methods:1.002 RA patients from two independent cohorts were included: 1) a prospective longitudinal cohort of early RA (5 years) (n=401) with inadequate response to methotrexate. Determinants of PGA were assessed by Pearson’s correlation coefficients and multivariable linear regression.Results:In early RA, median (IQR) symptom duration at inclusion was 15 (9-27) weeks, 71.5% of the patients were female, 49.3% were autoantibody-positive, and 30% had radiographic evidence of ≥1 erosion. The mean (SD) DAS28 was 4.94 (1.19), and the mean (SD) PGA 57.6 (26.6). The proportion of patients at least in low disease activity (DAS28 0.40) at all time points, and were independent of other co-variates (Table 1). Swollen joints (SJC28) were independently and directly associated with PGA at all time points until 12 months, whilst the association become indirect at 24 months (Table 1). In ACPA-positive patients, PGA at 6 and 12 months was weakly but still significantly associated with SJC28 even in low disease activity states (adj r 0.15 and 0.13, pConclusion:In established RA, PGA appears mostly related to factors outside the core domains of disease activity. In contrast, in the early phases of the disease, PGA may more strictly collect information on inflammatory-related symptoms. Better understanding of the relationship between patient reported outcomes and disease activity in the various phases of RA may thus be needed before introducing definitive changes in the current definitions of disease activity.References:[1]Nikiphorou E et al. Arthritis Res Ther 2016;18:251[2]Ferreira RJO et al. Ann Rheum Dis 2019;78:e109.Table 1.Associations of PGA in early RA at different time points0 months6 months12 months24 monthsr (95% CI)pr (95% CI)pr (95% CI)pr (95% CI)pVAS pain0.74 (0.70-0.77)0.83 (0.80-0.86)0.84 (0.80-0.86)0.83 (0.79-0.87)HAQ0.47 (0.41-0.54)0.54 (0.46-0.62)0.57 (0.50-0.63)0.50 (0.41-0.59)SJC280.27 (0.19-0.35)0.27 (0.18-0.35)0.21 (0.12-0.30)0.23 (0.13-0.33)TJC280.34 (0.27-0.41)0.39 (0.31-0.47)0.39 (0.30-0.46)0.30 (0.20-0.40)CRP0.08 (0.00-0.17)0.050.09 (0.00-0.19)0.070.19 (0.10-0.28)0.03 (0.09-0.14)0.63β standpβ standpβ standpβ standpVAS pain0.660.760.740.80HAQ0.200.180.010.200.030.220.003SJC280.170.030.150.040.110.04----TJC28----------------CRP------------Acknowledgements:I have no acknowledgements to declare.Disclosure of Interests:Ludovico De Stefano: None declared, Serena Bugatti Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos, Bernardo D’Onofrio: None declared, Ennio Favalli Speakers bureau: AbbVie, MSD, Novartis, Pfizer, UCB Pharma, Antonio Manzo: None declared, Roberto Caporali Speakers bureau: AbbVie, BMS, Celgene, HSD, Lilly, Pfizer, Roche, UCB Pharma, Carlomaurizio Montecucco Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos, Roche, Novartis

Background:Long-term observational data on the real-life use of JAK inhibitors (JAKis) for rheumatoid arthritis (RA) and their comparison with biological drugs are still very limited. Large population-based registries have been increasingly used to investigate the performance of targeted drugs in a real-life setting.Objectives:The aim of this study is to evaluate and compare the 3-year retention rate of JAKis, TNF inhibitors (TNFis) and biologic drugs with other mechanisms of action (OMAs) in the large cohort of RA patients included in the Italian national GISEA registry.Methods:Data of all RA patients treated with targeted synthetic or biologic drugs were prospectively collected in the Italian multicentric GISEA registry. The analysis was limited to patients who started a first- or second-line targeted drug in the period after the first JAKi was marketed in Italy (1st December 2017). The 3-year retention rate was calculated by the Kaplan-Meier method and compared between different drug classes by a log-rank test. A descriptive analysis of reasons for discontinuation was performed.Results:The study population included 1027 RA patients (79.8% females, mean age [±SD] 56.9 [±13.5] years, mean disease duration 9.8 [±9] years, mean baseline SDAI 17.5 [±11.9], ACPA positive 67.4%, RF positive 62.7%) who received JAKis (baricitinib or tofacitinib, n=297), TNFis (n=365), or OMAs (n=365) as first or second targeted drug. Main baseline characteristics of study population were overall well balanced between treatment groups. Retention rate was numerically but not statistically higher (p=0.18) in patients treated with JAKis compared with TNFis or OMAs (80.6, 78.9 and 76.4% at 1 year and 73, 56.8 and 63.8% at 3 years, respectively) (Figure 1). Drug survival was significantly higher in patients receiving concomitant methotrexate (MTX) compared with monotherapy only in TNFis (66.8 vs 47.1%, p=0.04) but not in JAKis (76.1 vs 70.1%, p=0.54) and OMAs (66.1 vs 61.9%, p=0.41) group. Therapy was discontinued in a total of 211 patients because of ineffectiveness (n=107), adverse events (n=88), or compliance/other reasons (n=16). The most frequent reason for treatment withdrawal was ineffectiveness in both JAKis (n=30 out of 56) and TNFis (n=45 out of 74) groups, whereas OMAs were discontinued more frequently because of adverse events (n=41 out of 81).Conclusion:Our data confirmed in a real-life setting a favorable 3-year retention rate of all available targeted mechanisms of action for RA therapy. As expected, concomitant MTX significantly impacted persistence on therapy of TNFis only. Discontinuations of JAKis for adverse events were infrequent overall, confirming the safety profile observed in randomized clinical trials.Figure 1.Three-year retention rate by treatment groupDisclosure of Interests:None declared

Background The optimal duration of remission-maintenance treatment in ANCA-associated vasculitis (AAV) is still unknown, 1 with International recommendations suggesting to maintain it for at least 24 months. Data supporting the correct balance between relapse risk, treatment-related adverse events and damage are highly needed. Objectives To analyse the frequency and predictors of withdrawal of remission-maintenance immunosuppressive drugs (IS) in a large real-life cohort of AAV patients. Methods Clinical records of patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were retrospectively analysed from a multicentric cohort. We divided the cohort into group A (withdrawal) and group B (ongoing). Results We included 185 patients. Forty-one patients (22%) had withdrawn IS at the end of follow-up (median 73.5 months, IQR 54–115). Concomitant glucocorticoids were stopped in 33%. There were no significant differences in AAV subtype, ANCA pattern, age at diagnosis, diagnostic delay or comorbidities rates between group A and group B (table 1). Disease onset with pulmonary involvement was significantly more frequent in patients in whom IS was maintained (69.7% vs 45%; p=0.004). Figure 1. Disease activity at onset, but not during follow-up, was significantly higher in patients from group B (ongoing): median BVAS 18 (12–24) vs 15; (8–20) p=0.02. The type of IS used for remission induction did not differ between the two groups. Maintenance treatment with Rituximab (RTX) was associated with higher probability of discontinuing IS by the end of follow-up (21% vs 7.6%; p=0.02). There was no difference in the number of major relapses between the two groups. Safety profile was equally good in both groups, except for a higher number of infections over the course of disease in patients who withdrew IS (5% vs 0). Vasculitis damage index (VDI) was comparable between the two groups. Conclusions IS withdrawal was observed in a minority of real-life patients with AAV. Drug-free remission was negatively associated with pulmonary involvement and higher BVAS at disease onset. Remission maintenance with RTX was associated with a higher frequency of drug withdrawal at the end of follow-up. Reference [1] Karras, et al. Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis. Ann Rheum Dis2017;76:1662–68 Disclosure of Interest None declared

Background In patients with rheumatoid arthritis (RA) increased mortality, especially for cardiovascular (CV) events, is still described, despite the advances in RA management. Objectives To evaluate the impact of early diagnosis and treatment with disease modifying anti-rheumatic drugs (DMARDs) on mortality in patients with early RA and undifferentiated arthritis (UA) through record linkage between clinical and administrative databases. Methods Consecutive patients with RA or UA from an early arthritis clinic (2005–2016), treated with tight control to achieve DAS28 6 months), from diagnosis to treatment ( 3 months, never) and from onset to treatment ( 6 months, never) on overall mortality. Analyses were adjusted for age, gender, ACPA positivity, Charlson comorbidity index, HAQ and median daily prednisone dose. Results were presented as hazard ratios (HR) with 95% CI. Secondary analyses categorising prednisone in low dose (≤5 mg/day) or medium-high dose (>5 mg/day) were performed, as well as analyses evaluating CV mortality as outcome. Moreover, analyses excluding patients not receiving DMARDs and patients dying in the first year of observation were conducted. Results A total of 857 patients (62% RA, 73% female, median (IQR) age 59,47–71 mean (sd) baseline DAS28 3.08 (0.97)) were included. After a median (IQR) follow-up of 8051–109 months, 77 patients died (2 in the first year); of the 41 patients with known cause of death, 9 were for CV causes. An interval >3 months between diagnosis and introduction of DMARDs or never introducing DMARDs related to higher mortality (table 1). The mean daily prednisone dose was not a significant predictor of mortality, while in all secondary analyses patients receiving low-dose prednisone, compared to those never receiving corticosteroids, had a lower mortality (eg. HR (95% CI) 0.45 (0.26,0.78) in the model including time between symptom onset and diagnosis). Patients not starting DMARDs, compared to these starting within 3 months from diagnosis, had a higher CV mortality), while the intervals between onset and diagnosis and onset and treatment were not significant predictors. Analyses limited to patients receiving DMARDs and with the exclusion of patients dying in the first year yielded to similar results. Conclusions In patients with early RA and UA treatment delay significantly increases mortality, while low-dose corticosteroids seem to decrease mortality. These result support strategies aiming at early access to treatment and the use of low dose corticosteroids in the initial treatment strategy. Disclosure of Interest None declared

Background Patients affected by ANCA associated vasculitides (AAV) show lower survival than general population, even if the mortality decreased significantly in the last decade. Objectives Aim of our study is to analyse the early mortality (within 6 months) and the long-term survival in a multicentric Italian cohort of AAV patients. Methods we identified all patients affected by AAV, diagnosed from 1995 until 2017, followed routinely in four vasculitis referral centres in Norther Italy. We enrolled patients with diagnosis of granulomatosis with polyangiitis (GPA) and micro polyangiitis (MPA), fulfilling EMA algorithm or CHCC 2012 definitions, with complete survival data at last follow up. The analysis focused on early mortality, long-term survival and their predictors. Results We enrolled 200 AAV patients (F/M 110/90, Caucasian 98%) with a median age at diagnosis of 54.6±15.2 years. 157 (78.5%) were affected by GPA and 43 (21.5%) by MPA. Data about ANCA antibodies were available in 181 patients and 157 (87%) resulted ANCA positive: 100 c-ANCA/PR3, 56 p-ANCA/MPO and one with double specificity PR3-MPO-ANCA. During the follow up period [5328–100 months], we registered 21 (10.5%) deaths, 6 (28.5% of all mortality) within 6 months after diagnosis: 9 patients died due to infectious complications, 1 due to hepatic cancer, 1 due to end stage heart failure, 1 due to massive cholestasis and 9 due to unknown causes. Early mortality was significantly associated with a higher frequency of alveolar haemorrhage (p=0.01; OR 11.1 IC95% 2.1–60.1) and respiratory failure (p The long-term survival, analysed with Kaplan-Maier method, did not show significant differences between GPA and MPA patients, while a significant poorer survival was observed in p-ANCA/MPO patients than c-ANCA-PR3 and ANCA negative patients (Log rank test: p=0.04). At univariate analysis of baseline data, deceased patients resulted older at disease onset (p=0.001) with more comorbidities (p Conclusions In this large cohort of Italian patients we confirm a higher short and long-term survival in AAV patient than reported in literature. Nevertheless, up to one third of deaths occurred within 6 months after diagnosis and infection diseases resulted the most frequent cause of death. Moreover, our data confirm the prognostic importance of ANCA pattern and the poor outcome of patient with severe lung and renal involvement. Disclosure of Interest None declared

Background Current guidelines recommend an early and intensive treatment in patients diagnosed with rheumatoid arthritis (RA), and the 2010 ACR/EULAR Classification Criteria were developed with the aim of allowing earlier diagnosis and treatment (1,2). Recent studies highlighted some differences in disease activity between seropositive and seronegative RA patients at disease onset (3). Objectives To investigate whether the application of the 2010 ACR/EULAR Classification Criteria and a more aggressive treatment strategy improve clinical outcomes in patients with early RA irrespective of the autoantibody status. Methods 584 early, treatment-naive RA patients were recruited in the years 2005–2014. RA diagnosis was made according to the ACR 1987 criteria in 2005–2010 (n=360, cohort 1987), and to the 2010 ACR/EULAR criteria in 2011–2014 (n=224, cohort 2010). Patients were classified in autoantibody (Ab)-negative (negative rheumatoid factor (RF) and/or anticitrullinated peptide antibody (ACPA) and Ab-positive (RF and/or ACPA positive). Methotrexate (MTX) was used at the initial dosage of 10 mg/week in cohort 1987, and 15 mg/week in cohort 2010, and progressively increased if low disease activity (LDA) (DAS28≤3.2) was not met. The frequency and predictors of LDA and clinical remission (DAS28 Results In Ab-negative patients, LDA and clinical remission were achieved in 62.8% and 37.2% of the cases, and the 2010 cohort did not show significantly improved outcomes (HR [95% CI] 0.86 [0.611.23] for LDA$;$ 1.04 [0.651.69] for remission) (Figure 1A,B). In contrast, in Ab-positive patients, the application of the 2010 classification criteria and higher dosages of MTX were associated with increased frequency of LDA after adjustment for confounders (age, sex, prednisone, baseline DAS28$;$ HR [95% CI] 1.39 [1.012]) (Figure 1C). Clinical remission was achieved in 41.3% of the cases, compared to 29.6% in the 1987 cohort (p=0.17) (Figure 1D). Conclusions Early diagnosis and a more aggressive treatment strategy with MTX lead to significantly improved outcomes in autoantibody positive RA. The management of seronegative patients remains suboptimal. References Smolen JS et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016. Aletaha D et al. 2010 rheumatoid arthritis classification criteria: an ACR/EULAR collaborative initiative. Ann Rheum Dis 2010. Nordberg LB et al. Patients with seronegative RA have more inflammatory activity compared with patients with seropositive RA in an inception cohort of DMARD naive patients classified according to 2010 ACR/EULAR criteria. Ann Rheum Dis 2017. Disclosure of Interest None declared

Background Remission is the current aim of early RA treatment. In patients with early, aggressive RA, combination with adalimumab (ADA) plus methotrexate (MTX) was superior to either MTX or ADA alone in obtaining clinical remission. Moreover, it has been demonstrated that a short-term aggressive treatment with high-dose glucocorticoids (GC) plus conventional DMARDs lead to long-term (up to 5 years) benefits. Objectives To compare the proportion of patients who achieve remission at 12 months, between two groups of subjects treated with ADA + MTX + high dose GC (intensive) and ADA + MTX + placebo (standard), and to evaluate the proportion of those maintaining remission at 24 months, after discontinuation of GC at 6 and ADA at 12 months. Methods The main inclusion criteria were: active RA, disease duration ≤1 year, GC and MTX-naivity, at least one predictor of aggressive disease. All subjects received ADA for 12 months and MTX (20 mg/w) to the end of month 24. Subjects were randomized to receive prednisone (orally, 50 mg/d, progressively tapered to 6.25 mg and stopped at month 6) or placebo. Response was evaluated using DAS28, CDAI, SDAI and ACR response criteria. The difference in rate and 95% CI will be computed with a binomial regression model and identity link, while clustering on center. An intention-to-treat analysis was performed. Results 118 patients were assigned to standard and 115 patients to intensive group. Remission (DAS28 Conclusions Our results confirm that intensive treatment with biologics in early, aggressive RA might be considered to induce and maintain clinical remission. The addition of high-dose GC to a first line treatment with ADA and MTX did not prove to induce a further improvement in efficacy. Although these results should be tested with other biologic therapies, the high rate of drop out for AE in the intensive group should be carefully considered in the risk-benefit ratio. Disclosure of Interest None declared

A Failure Mode and Effect Analysis (FMEA) at component level was done to study safety-relevant implications arising from possible failures in performing remote handling (RH) operations at ITER facility [1] . Autonomous air cushion transporter, pallet, sealed casks and tractor movers needed for port plug mounting/dismantling operation were analysed. For each sub-system, the breakdown of significant components was outlined and, for each component, possible failure modes have been investigated pointing out possible causes, possible actions to prevent the causes, consequences and actions to prevent or mitigate consequences. Off-normal events which may result in hazardous consequences to the public and the environment have been defined as Postulated Initiating Events (PIEs). Two safety-relevant PIEs have been defined by assessing elementary failures related to the analysed system. Each PIE has been discussed in order to qualitatively identify accident sequences arising from each of them. As an output of this FMEA study, possible incidental scenarios, where the intervention of rescue RH equipments is required to overcome critical situations determined by fault of RH components, were defined as well. Being rescue scenarios of main concern for ITER remote handling activities, such families could be helpful in defining the design requirements of port handling systems in general and on RH transfer system in particular. Furthermore, they could be useful in defining casks and vehicles to be used for rescue activities.

Onset of ANCA-associated vasculitis (AAV) can be abrupt with life-threatening manifestations requiring Intensive Care Unit (ICU) admission. A high level of suspicion leading to prompt diagnosis is essential. Our objective was to investigate the epidemiologic characteristics and the type of life-threatening manifestations.Medical records of AAV patients were analysed, selecting those with an ICU onset to identify predictive signs or symptoms and past medical history warnings useful for diagnosis.Out of 90 patients with AAV, 10 (11.1%) showed an ICU onset. The most frequent AAV diagnosed in the ICU was eosinophilic granulomatosis with polyangiitis (EGPA) (60%), followed by granulomatosis with polyangiitis (GPA) (20%) and microscopic polyangiitis (MPA) (20%). Cardio-pulmonary involvement was the main cause for ICU admission (70%) and significantly distinguished the ICU onset group from other AAV. The most frequent anamnestic warnings were history of asthma (50%), nasal polyps (30%), eosinophilia (30%). Symptoms shortly preceding ICU admission were arthralgia, fever (30%) and purpuric lesions (20%). ANCA were positive in 60% of patients. Mean Birmingham Vasculitis Activity Score (BVAS) at diagnosis was 16±8.43 and 0.88±1.45 at the end of follow up. All patients survived with a 10% rate of chronic kidney disease and a mean Vasculitis Damage Index (VDI) of 2±1.15.Keeping a high level of suspicion for AAV is mandatory, particularly when treating life-threatening onset manifestations in the ICU. A history of asthma, nasal polyps, eosinophilia and arthralgia should always be investigated. ANCA are negative in about half of cases, therefore clinical expertise and strict collaboration with the rheumatologist are still pivotal.

The complexity of the ITER (International Thermonuclear Experimental Reactor) plant and the inventories of radioactive materials involved in its operation require a systematic approach to perform detailed safety analyses during the various stages of the project in order to demonstrate compliance with the safety requirements. The failure mode and effect analysis (FMEA) methodology has been chosen to perform the safety analysis at system level for ITER. The main purposes of the work are: to identify important accident initiators, to find out the possible consequences for the plant deriving from component failures, identify individual possible causes, identify mitigating features and systems, classify accident initiators in postulated initiating events (PIEs), define the deterministic analyses which allow the possible accident sequences to be quantified, both in terms of expected frequency and radiological consequences, and consequently, to ascertain the fulfillment of ITER safety requirements. This paper summarises the FMEA performed for the heat transfer systems (HTSs).

The paper analyses the pressurization of the ITER cryostat during an ex-vessel loss of coolant accident (LOCA) in the first wall–shielding blanket (FW–SB) primary cooling loop. Since the cryostat is a strong barrier against the release of mobilized hazardous material, its integrity is essential in meeting the ITER safety objectives. The analyses refer to ITER TAC 4 design and were performed by means of a fast running thermal fluid dynamic code that allowed parametric studies. Helium LOCA can be handled by the code, so that the analyses did take into account phenomena such as coil quench and electrical arcing between coil turns, that may occur in tokamaks with superconducting cables in the magnet coils. The main result was that even in the worst conditions the pressure transient in the cryostat does not damage its integrity provided that the plasma facing components (PFC) cooling loops in the vacuum vessel remain undamaged. Hence, if no other energy sources than those coming from an ex-vessel LOCA are added to water, helium and heat structures in the cryostat, the cryostat maintains its integrity. More analyses are needed to evaluate an in-vessel LOCA and the consequent cryostat pressurization transient. In fact this event would add decay heat and exothermic chemical reaction as energy sources to be possibly taken into account in the pressurization transient. These analyses are not within the scope of this work.

This paper summarizes several investigations on the identification of possible multiple failure accidents relevant in terms of consequences for the SEAFP reactor. Particularly, on those sequences of events that could induce a risk of radioactive materials bypass through the SEAFP confinement barriers. The analyses here reported are related to the Heat Transfer Systems of both reactor models 1 and 2. The work is carried out within the Safety and Environmental Assessment of Fusion Power—Long Term Programme (SEAL) 95/96. A set of specific initiating events (IEs) has been individuated, on the basis of the previous studies performed in the frame of the first SEAFP program. Basing on pre-existing analyses, each accident initiator has been discussed and several sequences have been described depending on the additional failures which could follow the initiator.

Background The clinical phenotype of the antisynthetase syndrome (AS) has been related with the underlying autoantibody specificity. The typical disease triad (arthritis, myositis, and interstitial lung disease -ILD) is common in anti Jo-1 + AS, whereas isolated ILD is associated with anti PL-7 and PL-12 Ab. The majority of anti Jo-1 + patients without all triad findings at the onset (incomplete ASSD) will develop lacking features during the followup Objectives To assess the triad clinical spectrum time course in non anti Jo-1 + AS Methods The study cohort included patients + for anti-EJ, OJ, PL-7, or PL-12 Ab with at least 1 triad finding. Clinical features were retrospectively collected and analyzed Results we included 65 non anti Jo-1 + AS (7 anti EJ, 4 anti OJ, 30 anti PL-12, 24 anti PL-7; 49 females, 16 males). In median, age at disease onset was 53 years (IQR 42–64), diagnostic delay 9 months (IQR 3–23.5), followup 60 months (IQR 20.5–113). Patients9 characteristics are reported in Table 1. During the followup, 22/61 patients with incomplete AS developed new triad findings, in median 12 months (IQR 6–27) after disease onset. The frequency of incomplete AS developing new triad findings and the length of followup were significantly reduced in non anti Jo-1 + patients with respect to our corresponding anti Jo-1 + cohort (respectively: 22/61 vs 138/220, p Conclusions In non anti Jo-1 + patients the ex novo occurrence of classic triad finding is common, but less frequent than in anti Jo-1 + patients. The different length of followup may explain at least partly this difference References Cavagna L, et al. Medicine (Baltimore) 2015;94:e1144 Disclosure of Interest None declared

Background F8-IL10 (Dekavil) is a human immunocytokine composed of the vascular targeting antibody F8, specific to the extradomain A of fibronectin, fused to the cytokine interleukin-10. F8-IL10 is being investigated in a dose-finding, PK phase Ib study and in a randomized, double blind, placebo-controlled phase II study, as a new therapeutic strategy for rheumatoid arthritis (RA). Objectives The primary objective of the phase Ib study is to determine the safety, tolerability and MTD of Dekavil in combination with methotrexate (MTX). The primary objective of the phase II study is to assess the superiority of Dekavil plus MTX over MTX by measuring the mean change from baseline of DAS28-CRP. Immunogenicity of F8-IL10 and its PK and PD profile will also be explored. Methods Patients with active RA despite MTX therapy and who failed anti-TNFα treatment are the target population of both studies. In the phase Ib, cohorts of 3–6 patients are treated with escalating doses of Dekavil (6, 15, 30, 60, 110, 160, 210, 300, 450 and 600 μg/kg) in combination with a fixed dose of MTX (10–15 mg). In the phase II, patients are randomized to Dekavil 30 or 160 μg/kg plus MTX or placebo plus MTX. Dekavil is administered by s.c. injection once weekly for a maximum of 8 weeks in both studies. Results The first 9 cohorts of the phase Ib study have been completed, 32 patients were treated and 31 are evaluable for DLT. One DLT (G2 purpura) was observed in one patient of the 9th cohort. The same patient had G1 thrombocytopenia and G3 ALT increase. Both events were considered related to the study drug and resolved within ten days. Neither SUSAR nor treatment-related deaths occurred. Mild injection site reactions were reported in 59% of patients and 2 cases of anemia (G2 and G3) were considered related to the study drug. All adverse reactions resolved after the end of treatment. Currently, the MTD has not been reached and the 600 μg/kg dose is ongoing. To date, 59.3% of the 27 patients analyzed for efficacy had ACR and EULAR responses, 29.6% and 11.1% had ACR50 and ACR70, respectively, at the low dosages of 15, 30 and 60 μg/kg. Two patients benefited from ACR70 response for 12 months after the last drug administration. In the phase II study, 13 out of 87 patients have been enrolled so far. To date, neither SUSAR nor treatment-related deaths were recorded. Conclusions The promising safety and efficacy results, even at low dosages, of Dekavil in the phase Ib study led to the start of the phase II study to verify the efficacy of Dekavil in combination with MTX in the same patient population. The currently available data suggest that the targeted delivery of IL-10 to the sites of inflammation is a promising therapeutic approach for RA. Disclosure of Interest M. Galeazzi: None declared, R. Voll: None declared, G. Sebastiani: None declared, L. Bazzichi: None declared, O. Viapiana: None declared, J. Dudler: None declared, P. Sarzi-Puttini: None declared, E. Selvi: None declared, A. Iuliano: None declared, M. Pedretti Employee of: Philogen, L. Giovannoni Employee of: Philogen, I. Bindi Employee of: Philogen, C. Bettini Employee of: Philogen, N. Ravenni Employee of: Philogen, J. Wilton Employee of: Philogen, P. Zufferey: None declared, G. Ferraccioli: None declared, R. Caporali: None declared, C. Specker: None declared, J. Wollenhaupt: None declared, D. Neri Shareholder of: Philogen

Theoretical description of Brillouin scattering from shear horizontal (SH) acoustic surface phonons in a generic multilayer structure with arbitrarily smooth interfaces is given. To evaluate the p-s Brillouin cross-section, the SH phonon spectrum, the transmitted zeroth-order field and the fluctuating polarization vector radiating the Brillouin light are computed numerically by means of a method that can take into account any depth profiles of elastic, elasto-optic and dielectric properties of the medium including electromagnetic absorption. As an application the case of a silicon on insulator structure with both sharp and diffuse interfaces is illustrated.

Lo scorso settembre sono stati pubblicati i criteri classificativi 2010 ACR/EULAR per l’artrite reumatoide (AR) (1). La creazione del nuovo set di criteri e stata dettata da due principali motivi: in primo luogo dalla chiara evidenza dell’insufficiente accuratezza diagnostica dei criteri ACR 1987 nel discriminare pazienti con AR nelle fasi precoci di malattia (2); in secondo luogo dalla documentata necessita di una terapia precoce con disease modifying anti-rheumatic drugs (DMARDs) anche in forme di artrite indifferenziata per prevenire l’evoluzione della malattia (3, 4). Il grande elemento di novita emerso e rappresentato dalla formalizzazione di un nuovo concetto di AR. Nel precedente set di criteri del 1987 erano stati inclusi soggetti con diagnosi di AR di lunga durata e soggetti con altre artropatie, infiammatorie e non, ed erano stati testati una serie di criteri per identificare la migliore combinazione in grado di individuare pazienti con AR (5). Il concetto di AR alla base dei criteri classificativi del 1987 valorizzava aspetti di severita di malattia (fase avanzata), quali ad esempio erosioni e presenza di noduli reumatoidi, piuttosto che di sviluppo di malattia (fase precoce)...

Background F8-IL10 (Dekavil) is a fully human immunocytokine, composed of the antibody fragment F8, specific to the extradomain A of fibronectin (EDA-FN), fused to the anti-inflammatory cytokine interleukin-10 (IL-10) [1, 2]. F8-IL10 is currently being investigated as a new therapeutic strategy targeting the inflamed tissues in rheumatoid arthritis (RA). Objectives To determine the safety and tolerability of Dekavil when administered in combination with methotrexate (MTX) to patients suffering from RA who had failed at least one anti-TNFα drug therapy. To give a preliminary evaluation of the efficacy of Dekavil when administered in combination with MTX. Methods A Phase Ib non-placebo controlled clinical trial is currently ongoing in order to establish the maximum tolerated dose (MTD) of Dekavil when administered in combination with MTX. Cohorts of 3-6 patients are treated with escalating doses of Dekavil (6, 15, 30, 60, 110, 160, 210, 300, 450 and 600 μg/kg) in combination with a fixed dose of MTX. Dekavil is administered by subcutaneous injection once a week for a maximum of 8 weeks. Results As of today, the first eight cohorts of the study have been completed (dose levels from 6 to 300 μg/kg). Twenty-six patients are evaluable for safety. No dose limiting toxicities nor serious adverse events have been recorded. No MTD has yet been reached; the dose level of 450 μg/kg is currently ongoing. Mild injection site reaction has been reported in 54% of patients. Regarding systemic adverse reactions, one case of progressive anemia was reported in one patient treated at 160 μg/kg. All adverse reactions resolved after the end of treatment with minor or no therapeutic interventions. A therapeutic benefit of Dekavil, in terms of ACR response, has been recorded in the treated patients, even in subjects treated with low drug dosages. To date, 25 patients are evaluable for efficacy. Among this population, ACR20, 50 and 70 responses were achieved by 60%, 32% and 16% of patients, respectively. In addition, two patients treated at 30 μg/kg and 60 μg/kg dose levels achieved a long-lasting remission. Conclusions The promising safety profile, together with the preliminary efficacy responses in this non-placebo controlled trial led to the start of a Phase II placebo-controlled trial within the same patient population to verify the efficacy of low dosages of Dekavil in combination with MTX. The currently available data suggest the targeted delivery of IL-10 to the sites of inflammation is a promising therapeutic approach for RA. References K. Schwager et al. (2009) Arthritis Res. Ther., 11, R142 F. Doll et al (2013) Arthritis Res. Ther., 15, R138 Disclosure of Interest M. Galeazzi: None declared, G. Sebastiani: None declared, L. Bazzichi: None declared, E. Garcia Gonzalez Consultant for: Philogen, N. Ravenni Employee of: Philogen, L. Giovannoni Employee of: Philogen, J. Wilton Consultant for: Philogen, E. Selvi: None declared, M. Bardelli: None declared, C. Baldi: None declared, A. Iuliano: None declared, G. Minisola: None declared, R. Caporali: None declared, S. Bombardieri: None declared, D. Neri Shareholder of: Philogen

Background Actually, as suggested from current therapeutic guidelines, tapering of biologic agents (bDMARDs) seems a feasible option in subsets of rheumatoid arthritis (RA) patients in persistent clinical disease control [1]. However definite step-down schedules are far to be fully elucidated due to the heterogeneity of available data in controlled trials. Data on real life contests are even fewer. Objectives To analyze the feasibility of bDMARD spacing in maintaining clinical disease control in real life RA patients in persistent low disease activity (LDA) or remission. To monitor sub-clinical signs of disease activity during bDMARDs tapering. Methods RA patients in persistent clinical disease control (at least LDA according to DAS28 score for at least 6 months) underwent current bDMARD (anti-TNF/no anti-TNF agents for at least 1 year) spacing (doubling of the inter-administration time); concomitant co-medications (conventional synthetic DMARDs/csDMARDs and/or low dose oral corticosteroids/CS) were carried on at stable dosages. Clinical and ultrasonographic (US) assessments were performed bi-monthly over initial 6 months period in order to define clinical relapse (> LDA) and to monitor clinical and sub-clinical signs of inflammation (Gray scale, GS, and power Doppler, PD scores detected on hand and wrist US examination). Results about first 4 months of follow up are yet available for preliminary analysis. Results Globally, 35 patients met the criteria and agreed to the spacing. Most of them had an established disease (mean duration ± sd 11,92±7,80 years) with markers of poor prognosis (57% seropositive patients, 60% patients with erosive disease). They were generally on their first anti-TNF bDMARD therapy (30 anti-TNF, 4 tocilizumab, 1 abatacept) together with csDMARDs co-medication (29/35 patients); they were mostly CS free (28/35 cs-free patients; 7 patients on low dose oral CS). Over 4 months of observation DAS28 score did not significantly change (mean value ± sd from 1,92±0,59 to 1,89±0,63, p not significant), as happened for GS score (median [IQR] from 9 [8-12] to 11 [9-13], p not significant). Median PD score [IQR] significantly increase over time, from 0 [0-0] at baseline examination to 1,5 [0-4] (p=0,01) at 4 months. In 4 months, globally 2 patients relapsed. Conclusions Biologic DMARDs spacing might be a possible therapeutic option in real life RA patients in persistent disease control: despite the substantial increase in PD score, few patients clinically relapsed in the first months of observation. For a complete evaluation, risk-to-benefit issues should involve long-term clinical, functional and structural outcomes, along with safety and financial issues too. Predictive factors need to be fully elucidated to target patients who might benefit more from this strategy. References Smolen JS, et al. Ann Rheum Dis 2014;73:492–509. Disclosure of Interest None declared

Rheumatic diseases have an economic impact of 1-2.5% of GDP in industrialized countries and osteoarthritis is the most common joint disorder. Osteoarthritis of the knee is especially common and is a major cause of disability requiring extensive utilization of health care resources.To estimate the burden of osteoarthritis of the knee in Italy, we studied retrospectively a cohort of 254 patients over a period of 12 months in 2000-2001.Twenty-nine rheumatology institutes took part in the study. A bottom-up approach was used, analytically measuring pro capita consumption. We considered medical (hospitalization, diagnosis, and therapies) and non-medical costs (transport, temporary caregivers, and auxiliary devices) as direct costs. We calculated losses of productivity borne by patients and caregivers, and informal care provided by caregivers as indirect costs.Direct costs came to Euros 934 per patient per year: Euros 233 were spent on hospitalization, Euros 209 on diagnostic procedures (56% on visits and 44% on instrumental and laboratory tests), Euros 146 on therapy (58% on physiotherapy and 42% on drugs), and Euros 346 on non-medical costs (73% on salaries to temporary caregivers, 14% on transport, and 13% on auxiliary devices). It is interesting to point out that at least 37% of costs were charged directly to patients. Indirect costs were almost 30% higher and came to Euros 1236 per patient per year: 31% was due to loss of productivity of patients, 60% due to informal care provided by primary caregivers, and 9% by other caregivers.This study confirms that the direct and indirect costs attributable to osteoarthritis of the knee are substantial.

In Italy in 2003, 617 cases of legionellosis were reported to the national surveillance system, maintaining the recent increase seen first in 2002. The characteristics of the patients were very similar to those reported in 2002

To assess the frequency and clinical correlates of the systemic sclerosis-related autoantibodies to RNA polymerases in Italian patients.Sera from 115 patients with systemic sclerosis (SSc) and 10 patients with systemic sclerosis-overlap syndromes recruited from a single center in northern Italy were investigated for antibodies to RNA polymerase I, II, and III by means of immunoprecipitation using 35S-labeled HeLa cell antigen extract. Twenty-five normal volunteers and 91 patients with different connective tissue diseases were studied as a control group.Antibodies to RNA-polymerases were found in 14/115 SSc patients (12.1%). None of the normal controls and none of the patients with other connective tissue diseases, including overlap syndromes, were positive. Antibodies reacting with RNA-polymerase I and III (+/- RNA-polymerase II) were found in 9/115 patients (7.8%) and were mutually exclusive with respect to other scleroderma-related autoantibodies. Isolated anti-RNA polymerase II reactivity was found in 5 patients and was associated with anti-topoisomerase I antibodies in 4 cases. Anti-RNA-polymerase I and III antibodies were associated with diffuse cutaneous involvement and male gender. Only two patients from our series had scleroderma renal crisis, and one of them had anti-RNA polymerase antibodies.Anti-RNA-polymerase antibodies appear to be less frequent in Italian patients than in Caucasian patients from the United Kingdom or USA. This might be associated with the lower frequency of scleroderma renal crisis.

As part of a general safety study of a NET (Next European Torus)-type machine, the magnet system has been analyzed in order to identify all the malfunctions which may initiate accident sequences in the plant. The analysis addresses both toroidal and poloidal coils (including control coils). The main functions of each magnet subsystem are defined through a functional analysis. Based on this, an FMEA (failure made and effects analysis) has been done to identify the possible failures and related consequences for plant safety. The initiating events which have been identified are toroidal field and poloidal field coil quench, arcing due to coil damage, loss of power to some coils, LOCA (loss-of-coolant accident) in helium pipes, and poloidal field and toroidal field coil break. An event tree has been developed for each one of the initiating events, having mitigating features as headings and plant status classes with related frequencies as outcomes. A preliminary evaluation of the releases related to each accident class has been performed. Remarks and preliminary recommendations on system design are reported. >

Data on the origin and biological function of procalcitonin, the pro-hormone of calcitonin, are scarce. Since this peptide can be induced in bacterial invasive infections, serum procalcitonin levels may be useful in differential diagnosis of systemic inflammatory response syndrome. This review will focus on the clinical significance of changes in serum procalcitonin levels in patients with connective tissue diseases and other rheumatic disorders.

The possible failures and related consequences on plant safety for the NET (Next European Torus) system have been analyzed. The event tree initiators which have been identified are superconductivity quench propagation, short circuit and arcing due to coil damages and coil breaks, loss of power to some coils, loss of coolant accident (LOCA) in helium pipes, and loss of isolation vacuum (LIVA) in the cryostat. The authors present a discussion of the LIVA sequence, which represents a possible cause of coil generalized overheating. An ingress of water into the cryostat is assumed as a consequence of the rupture of a divertor cooling system line. Due to the fast and nonuniform overheating of the coil, some conductors can break, allowing helium to spill into the cryostat and, at the same time, generating electrical arcs in series connection. The energy dumping system is assumed to fail. Helium entering the cryostat is heated and can pressurize the cryostat. A parametric study has been performed to evaluate the cryostat pressure transients. >

An essential part of the Engineering Design Activities (EDA) for the International Thermonuclear Experimental Reactor (ITER) is the assurance that the design meets strict safety criteria. Analyses have been performed of postulated accidents, in order that the possible consequences can be assessed against targets for releases and other criteria. The range of events considered is based on studies which use systematic techniques to provide a comprehensive identification of potential accident initiators and sequences. Two independent and complementary approaches have been employed, illustrated here by a portion of a global fault tree and a sample event tree. The result of these studies is a demonstration that the ITER accident analyses treat a comprehensive range of event sequences, and give confidence that the ITER engineering design will achieve its safety targets.

Objective: to evaluate the effectiveness of fundoscopy, electrooculography, electroretinogram and visually evoked potentials in early detection of hydroxychloroquine retinal toxicity in RA patients and to evaluate the influence of patients’ age, drug dosage, concomitant therapy (prednisone and methotrexate) and serum creatinine levels in the development of this side effect. Methods: from september to december 1999, we have enrolled 32 RA patients (13 males, 19 females) starting hydroxichlorochine treatment. The patients underwent regular ophthalmological examination (fundoscopy, electro-oculography, electro-retinogram and visually evoked potentials) every 4 months. Disease activity was evaluated every two months by clinical and routine serological examination. Results: no patients developed retinopathy during 1 year’s follow-up; fundoscopy, electrooculography, and visually evoked potentials did not vary from the baseline. On the other hand, electroretinogram showed early alterations of scotopic and photopic response; moreover a significant statistical correlation between patients’ age (more than 65 years) and b1 photopic wave increase (p < 0,05) was observed. No correlation was found between the developement of electro- retinographic alterations and hydroxychloroquine dosage, concomitant therapy and serum creatinine levels Conclusion: our data show the inefficacy of fundoscopy, electrooculography and visually evoked potentials in early detection of hydroxychloroquine retinopathy. On the other hand electroretinogram allows early detection of retinal alterations during hydroxychloroquine treatment, in patients older than 65 years.

Background The relationship between systemic rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) and various comorbidities has long been debated, and it has also been observed that patients with RA and SpA develop adverse events during anti-TNF therapy. Objectives The primary aim of this multicenter study was to identify the most frequent comorbidities and adverse events (AEs) in RA, PsA and AS patients on the basis of the data in the LORHEN register. The secondary aim was to identify the effect of biological anti-TNF on adverse events development. Methods The study involved 2253 patients with RA (mean age 46.21±14.7 years; mean disease duration 14.8±8.9 years; F(%)=82.0%), 372 with long-standing PsA (mean age 41.2±13.5 years; mean disease duration 11.6±7.6 years; F(%)=38.3%), and 410 with AS (mean age 36.8±13.3 years; mean disease duration 11.6±8.9 years; F(%)=47.7%), all of whom had been treated with biological drugs for at least six months or had discontinued therapy due to serious adverse events. Of the RA patients, 34.4% had been treated with two DMARDs before receiving biological therapy, whereas the majority of PsA and AS patients had been treated with only one DMARD (respectively 40.22% and 39.85%). Many patients were treated with low-dose corticosteroids (

To evaluate the clinical and serologic profile, the rate of progression to well defined CTD and the possible predictors of disease evolution in patients affected by UCTD with antibodies anti-RoISSA.148 patients diagnosed as UCTD were retrospectively evaluated. Antibodies to SSA/Ro were determined by counter-immunoelectrophoresis and ELISA.Thirty-six patients (24.3%) developed a well-defined CTD after a mean follow-up of 4.5 years. Most patients developed primary Sjögren's syndrome (SS) (50%) or systemic lupus erythematosus (SLE) (30.5%). Leukopenia and xerophthalmia developed more frequently in the group of patients evolving to defined CTDs (p0.0032 and p0.0063). Leukopenia independently predicted the evolution in CTD by multivariate regression analysis (p0.019). Anti-dsDNA predicted the evolution in SLE (p0.0207), while the presence of additional anti-ENA specificity to anti-Ro/SSA was not associated with the outcome.24.3% of patients with UCTD and antibodies to Ro/SSA can progress in a relatively short period of time to well-defined CTDs. The development of primary SS could be predicted by xerophthalmia and SLE by the appearance of anti-dsDNA antibodies.

In this study we evaluated the efficacy of Infliximab in the treatment of adult Still's disease (ASD) refractory to conventional therapy. Three patients with chronic and active ASD unresponsive to corticosteroids and methotrexate were given intravenous Infliximab infusions at a dosage of 3 mg/kg at weeks 0, 2, 6 and then once every 8 weeks. Methotrexate was maintained in all cases at a dosage of 15 mg/week, whereas the prednisone dose was modified according to disease activity. The follow-up lasted 50 weeks and disease activity improved in all cases during Infliximab therapy. Two patients presented arthralgias and sore throat at 20 and 28 weeks, that was rapidly controlled by Infliximab reinfusion every 4 weeks. One patient relapsed at 18 weeks and dropped out at 22 weeks due to an urticarioid rash after the beginning of the fifth infusion. Infliximab may be effective in the treatment of relapse of ASD refractory to conventional therapy and requiring continuous high dose corticosteroid medication. Further studies are needed to evaluate the long-term safety, efficacy and the optimal schedule of infusion.

Autoantibodies to Ro(SS-A) may recognize two different polypeptides, of 52 kDa and 60 kDa, respectively. We used an ELISA with purified human recombinant antigens to conduct a detailed analysis of the specificities of anti-Ro(SS-A) antibodies from 170 patients with definite diagnoses (systemic lupus erythematosus [SLE], n = 55; primary Sjögren's syndrome [PSS], n = 39; systemic sclerosis, n = 9; rheumatoid arthritis [RA], n = 10) or undifferentiated connective tissue disease (UCTD, n = 57). Most of the patients with SLE or PSS had both anti-52 kDa and -60 antibodies; isolated anti-60 kDa antibodies were found in 13% of the SLE patients and in none of the PSS patients, whereas high titers of anti-52 kDa were more common in the PSS than in the SLE patients. In the UCTD patients, the anti-Ro(SS-A) profile showed no significant correlations with clinical features but was associated with the clinical outcome. Over the mean follow-up of five years, definite SLE developed in four of the five UCTD patients with isolated anti-60 kDa vs only one of the remaining 52 patients (P0.0001); progression to PSS was seen in seven of the 34 patients with both anti-52 kDa and anti-60 kDa vs none of the remaining 23 patients (P = 0.03); none of the 12 patients with isolated anti-52 kDa developed a definite connective tissue disease.Our study suggests that analysis of anti-Ro(SS-A) specificity may provide useful information for predicting the course of UCTD.

To measure serum and synovial fluid (SF) levels of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in patients with juvenile rheumatoid arthritis (JRA) and to compare them with adult rheumatoid factor-positive rheumatoid arthritis (RA).IL-8 and MCP-1 were measured by immunoassay (1) in sera obtained from 55 children with JRA and from 16 adults with RA, and (2) in SF obtained from 30 children with JRA and 11 adults with RA.Patients with active systemic JRA had serum levels of IL-8 and MCP-1 higher than in controls (p0.01) and in patients with active polyarticular or pauciarticular JRA (p0.05). In patients with RA serum MCP-1 levels were higher than in patients with the 3 JRA onset types, while no difference was found for IL-8 levels. Patients with systemic JRA and with current systemic features had serum levels of IL-8 and MCP-1 higher (p = 0.03 and p = 0.04, respectively) than patients in which systemic features had subsided. No significant differences in SF IL-8 or MCP-1 levels were found among the 3 JRA onset types or adults with RA. In patients with JRA SF leukocyte counts were correlated with SF IL-8 levels (p = 0.002), but not with MCP-1 levels. Moreover, SF levels of both IL-8 and MCP-1 were correlated with those of IL-1beta (p0.001) and IL-6 (p0.01), but not with those of TNF-alpha.Elevated serum levels of IL-8 and MCP-1 in patients with systemic JRA with current systemic features at sampling suggest systemic production of the 2 chemokines during systemic phases of the disease. Similar SF levels of IL-8 and MCP-1 among the 3 JRA onset-types and RA suggest comparable local production of the 2 chemokines.

The 7-valent anti-pneumococcal conjugate vaccine (PCV), anti-meningococcal C-conjugate vaccine (MenC) and varicella vaccine have been recently introduced in EU. In Italy, these vaccines have so far been recommended for use in specific groups. Since the health system is decentralised, the Regional Health Authorities (RHAs) can decide to recommend vaccination for other target populations. We conducted a survey to describe the recommendations on these vaccines currently in place in the 21 Italian regions. In November 2005, a standardised questionnaire was sent to RHAs, including information on the existence of regional recommendations, vaccination target population, and whether vaccines were provided free of charge, or at a reduced cost compared to pharmacies. Information reported in the questionnaires were followed up in May 2006. All 21 regions completed and returned the questionnaire and were contacted for follow-up. Recommendations about at least one of the three vaccines were present in 20 out of 21 regions. All included free of charge PCV offering to specific groups, while MenC and varicella immunisations were recommended in 17 and 19 regions, respectively. Recommendations for other individuals varied greatly by area: free of charge PCV and MenC vaccinations targeting all infants have been recommended in nine regions, and varicella vaccination targeting children in the second year of life in three regions. These different recommendations can lead to marked variation in vaccination coverage rates observed through the country, with a consequent different level of disease control. It is thus crucial to properly monitor vaccination coverage rates for PCV, MenC and varicella, as these are not routinely collected at the national level.

The computation of the Brillouin cross section for scattering of light off longitudinal acoustic (LA) bulk phonons in a superlattice with diffuse interfaces between the layers is presented for the case of normal incidence. Unlike in previous work concerning the problem of diffuse interfaces, both the modulation of the acoustic and elasto-optic parameters, and the modulation of the refractive index are taken into account. The acoustic phonon spectrum is computed by means of numerical solution of a self-adjoint Liouville equation, and the dispersion relation is obtained using a wavevector selection rule. The transmitted (zeroth-order) electromagnetic wave, and the consequent fluctuating polarization vector field radiating Brillouin light are computed numerically for generic depth profiles of elastic, elasto-optic, and dielectric (optic) properties of the medium. The back-scattered light wave in the superlattice is obtained to first order in perturbation theory. The Brillouin differential cross section is computed by summing over the density of phonon states satisfying the wavevector selection rule. As an application, we present some results for the GaAs - AlAs superlattice, providing evidence for the differences from the case with diffuse and sharp interfaces.

Background Anti-synthetase syndrome (AS) is a connective tissue disease characterized by myositis, arthritis, interstitial lung disease (ILD) and the presence of anti-synthetase antibodies, mostly anti-Jo-1. Patients with an incomplete form of AS have been described; however it is not known whether and when these patients will develop a full-blown clinical picture during the course of the disease Objectives To evaluate whether and how the clinical spectrum of patients with a diagnosis of incomplete AS changes during follow-up Methods All patients with anti-Jo-1 positive AS followed at our Department from 1991 were retrospectively evaluated for clinical features at the time of diagnosis and during follow-up. All patients had been regularly followed at our department. Two patients died during follow-up (after 57 and 106 months), whereas two patients were lost to follow-up after 92 and 118 months. All the remaining patients had their last visit after August 2011. Anti-Jo-1 positivity was confirmed in stored frozen sera from all patients using EliA Jo-1 fluoroenzyme-immunoassay (Phadia 250 automatic instrumentation, Phadia GmbH, Freiburg, Germany) Results For the purpose of this study, 18 patients (5 males/13 females) were analyzed. Median age at onset was 52.5 years (IQR 45-69) and median follow-up was 75 months (IQR 38-95). At the time of diagnosis, 8 patients (44%) had a complete form. The remaining 10 patients had an incomplete form; 5 had isolated arthritis, 3 arthritis and ILD, 1 arthritis and myositis and 1 had isolated ILD. At the last follow-up visit, a complete form of the disease was present in 14 patients (78%). Five patients with isolated arthritis developed both myositis and ILD within 3 months to 13 years, and 1 out of 3 patients with arthritis and ILD developed myositis after 2 years. Finally, the patient with isolated ILD developed arthritis after 21 months Conclusions Clinical presentation of anti-Jo-1 AS is quite variable as only 44% of patients had a complete form at onset. In particular, myositis was present in 50% of the patients diagnosed at our department and ILD in 67%. A long and careful follow-up is mandatory in patients with incomplete syndrome as myositis and ILD may occur even very late during the course of the disease Disclosure of Interest None Declared

Background Data from national surveys and general practitioner databases has shown an increasing prevalence of gout in several countries. However there is no data regarding the epidemiology of gout in Italy in the last decade. Objectives To assess both prevalence and incidence of gout in Italy between 2005 and 2009. Methods Data was obtained from the Italian primary care database (Health Search/Longitudinal Patient Database) which comprises about one million adults (>18 years) from all around the Country. Rates together with 95% Confidence Interval (CI) have been measured overall and stratified by age, gender and calendar year. Characteristics of patients with newly diagnosed gout and hyperuricemia have been explored Results Calculated prevalence of symptomatic gout increased from 6.7 per 1,000 adults in 2005 to 9.1 in 2009, whilst incidence remained stable (0.93 per 1,000 Person Years (PYs) in 2005 and 0.95 in 2009). Prevalence increases with age and is 4 times higher in males. A similar trend was observed for hyperuricemia whose prevalence is about ten times higher than that of symptomatic gout (66.3 per 1,000 adults in 2005 and 92.1 in 2009) in our population. Therefore during the study period, the prevalence of gout and hyperuricemia appears to be always slightly higher in the Northern Italy than in the Central and Southern Italy (e.g. year 2009: gout=9.3 vs. 8.6 vs. 9.0 per 1,000 inhabitants; hyperuricemia=95.3 vs. 92.7 vs. 88.0 per 1,000 inhabitants. Recurrent gout attacks were observed in 19.1% cases within one year following the first attack and in 23.1% cases within five years. Conclusions This is the first study regarding the epidemiology of gout in Italy. The overall prevalence of both gout and hyperuricemia is remarkably lower than that reported in similar population-based investigations carried out in other western countries, namely the US, UK and Germany. This difference might in part be related to country specific diet; in fact the typical Italian diet (i.e. Mediterranean diet) is associated with low levels of serum urate. Interestingly, the prevalence of gout and, to a lesser extent, of hyperuricemia is quite different across Italian geographic areas, with the higher figures observed in the Northern Italy. This finding is likely to be attributed to different dietary habits as the adherence to Mediterranean diet is higher in Central and Southern than Northern Italy High recurrence of attacks was observed during the first year following the first episode. References Roddy E, Doherty M. Arthritis Res Ther 2010;12:R223 Cea Soriano L, et al. Arthritis Res Ther 2011;13:R39 Zhu Y, et al. Arthritis Rheum 2011;63:3136-41 Annemans L, et al. Ann Rheum Dis 2008;67:960-6 Disclosure of Interest None Declared

Objectives To validate the EULAR scores for assessment of primary Sjogren’s Syndrome (SS): the EULAR SS Disease Activity Index (ESSDAI), the EULAR SS Patient Reported Index (ESSPRI). Methods Prospective international validation study with 2 visits: baseline and 6 months. At each physicians completed ESSDAI, SS disease activity index (SSDAI), Sjogren’s Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Construct validity (using correlations with gold standard), responsiveness (using standardized response mean [SRM]) and reliability (intraclass correlation coefficient [ICC]) were evaluated and compared between each scores. Results 395 patients (96% women, mean age 55.4 ± 13.7 years, 79% with anti-SSA and/or anti-SSB antibodies) from 15 countries have been included. At enrollment, 145 (37%) and 251 (64%) had, respectively, current or either current or past systemic manifestations. EULAR scores had higher correlation with gold standard than other scores (ESSDAI with PhGA: rho=0.59; ESSRPI with PGA: rho=0.70). Correlations between patient and systemic scores were very low (rho ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients (SRM= 0.69 to 0.82). Responsiveness of patients scores was low in patient experiencing improvement of their symptoms but was significantly higher for ESSPRI compared to SSI and PROFAD ((SRM=0.37 vs. 0.04 and 0.16; p=0.006 and 0.049 for SRM comparisons). Reliability was assessed in a subgroup of 47 and 62 patients, for systemic and patients scores, respectively. Reliability was very good for all scores (ICC=0.83 to 0.96). Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores were sensitive to change in patients whose disease activity improves. Patient scores had a small sensitivity to change. However, ESSPRI was significantly better than SSI and PROFAD. The poor correlation between systemic and patients scores confirms that these 2 components are different and should be evaluated separately. Disclosure of Interest : None Declared

Background The atypical chemokine receptor D6 is an inflammatory CC-chemokine scavenger. It is involved in resolution of inflammatory responses and leukocyte trafficking from sites of injury to secondary lymphoid organs through its expression on lymphatic endothelial cells and leukocytes. Peripheral blood mononuclear cells (PBMC) from Systemic Sclerosis (SSc) patients show a marked upregulation of D6 transcript and protein, functionally relevant in buffering CC-chemokines in the circulation. Objectives To investigate D6 expression and its potential roles in the skin of SSc patients Methods Patients with diagnosis of SSc according to Leroy’s criteria for limited cutaneous (lc), diffuse cutaneous (dc) or early disease, and healthy controls (HC), both consenting to the study according to local ethic committees, were enrolled. They underwent complete clinical evaluation, paired PBMC extraction and a skin punch biopsy on the forearm. Both cells and tissues were used for transcriptional analysis by real-time qPCR with standard curve quantification method. Transcripts were normalised to TATA-Binding Protein expression in PBMCs, to beta-actin in skin. Skin sections were double stained in immunofluorescence with anti-human D6 (R&D or Sigma) and markers of lymphatic endothelial cells (anti-human podoplanin, Sigma), or of hematopoietic derived cells (anti-CD45, Dako) and analysed by microscopy. Results The study enrolled a total of 19 patients (mean age 57.6±15 years, 18 Females, 4 early-SSc, 12 lc-SSc and 3dc-SSc). D6 transcripts in skin were significantly upregulated in SSc patients (3443±1761 vs 1035±327 in control skin, n=9, p 2 in SSc patients, D6 protein expression was detected with no significant difference on a mean percentage of 63±15% podoplanin+ lymphatic endothelial cells in patients and HC, while D6+ leukocytes were found only on a subset of patients and HC and their presence was apparently not related to any clinical feature. D6+ leukocytes were significantly more frequent in tissues of higher CD45+ infiltration. There was a trend toward an inverse relationship between D6 expression on lymphatics and CD45+ leukocyte infiltration on the skin, being the latter higher where there was less D6 on lymphatics. Conclusions Expression of the atypical CC-chemokine receptor D6 is upregulated in SSc skin and even in early phases of the disease. Its expression is higher in patients with lower mRSS scores indicating that it could represent an attempt to restrain local pathological activity. Inverse relationship between presence of D6 on lymphatics and leukocyte infiltration confirms this is a critical molecule in the regulation of trafficking to secondary lymphoid organs. Disclosure of Interest None Declared

Background Fibromyalgia (FM) is an heterogeneous and complex condition that deeply impact the quality of live of affected patients. Moreover FM imposes also a significant economic burden on society, mainly driven by indirect costs from lost productivity. FM treatment is based on a multidisciplinary approach, with a combination of pharmacological and non-pharmacological therapies. As indicated in the EULAR recommendations for the treatment of FM, individual tailored exercise programs, including aerobic exercise and strength training, can be beneficial in these patients; although this point has been confirmed in several studies, the adherence to various kind of exercise’s programs is generally poor when the patients had to exercise on their own. Objectives To evaluate the effectiveness and patients’ adherence to a simple program of home-made stretching exercises in fibromyalgia. Methods We enrolled all FM patients (ACR 1990 classification criteria), referring consecutively to our outpatients clinic from March to June 2011 and on stable treatment in the previous 6 months. Patients were randomly allocated in 2 groups. Group 1 was trained in a simple home-made stretching program based on 8 exercises; patients were asked to perform at least 4 exercises, for at least 20 minutes, for at least 3 days a week. Paper supports with explanations and cartoons representing exercises were handed to all these patients; moreover the patients were asked to sign in a daily diary the exercises performed and the time employed. Group 2 was first motivated about the effectiveness of a correct physical activity and then asked to perform stretching exercises, scheduled similarly to group 1 . No treatment changes were planned in both groups. A well validated questionnaire, Fibromyalgia impact questionnaire (FIQ), was used as outcome measure; FIQ was assessed at baseline and then after three months of exercises; results were analyzed by the Paired-Samples T Test. Adherence of patients to the program was also evaluated. Results We enrolled 44 patients, 22 in group 1 (mean age 46.8 years, standard deviation ± 10 years) and 22 in group 2 (mean age 47.7 years, standard deviation ± 10.5 years). Mean basal FIQ was 70 (standard deviation ± 18) in group 1 and 68 (standard deviation ± 19) in group 2 . After 3 months FIQ was significantly reduced in group 1 (mean value 45, standard deviation ± 15, p value 0.001), whereas no substantial changes were observed in group 2 (mean value 69, standard deviation ± 18, p value 0.232). Program adherence in group 1 was 100% (at least 6 exercises for at least 30 minutes in each training section; at least 4 training section every week); group 2 patients did not perform any kind of exercises. Conclusions Our results indicate that an easily designed program of home-made stretching may improve the impact of FM on affected patients. The enhancement of adherence with an extended support program (eg direct explanation of exercises, cartoons representing the exercises, report of training sections in a diary) is the key point for FM patients improvement. References Wolfe F, et al. Arthritis Rheum 1990;33:160-72. Salaffi F, et al. Clin Exp Rheumatol 2009;27:S67-74. Sarzi-Puttini P, et al. Clin Exp Rheumatol 2003;21:459-64. Carville SF, et al. Ann Rheum Dis 2008;67:536-41. Disclosure of Interest None Declared

Background HAQ (Health Assessment Questionnaire) is related to working ability, the need for specialist examinations and the quoad vitam prognosis; so it is an appropriate means of summarising outcomes, as well as the direct and indirect costs of the disease, as has been shown by pharmacoeconomic analyses. Moreover evenafter 20 years of treatment with traditional or biological DMARDs, joint damage evaluated using the Larsen and Sharp score isless than 40% of the highest possible score and the reversibility of the HAQ score is close to 70%even in the case of late arthritis. Objectives This article describes the findings of an observational study designed to evaluate disability in patients with long-standing rheumatoid arthritis (RA) treated with anti-TNF agents. Theaims were to define the main predictors of disability during biological treatment and assess treatment strategies (the use of steroids and traditional DMARDs, a switch to another anti-TNF agent). Methods The study involved 1033 patients attending six Italian rheumatology departments, who werestratified on the basis of various clinical and demographic variables. Drug effectiveness was assessed by analysing disease functional status using the Health Assessment Questionnaire (HAQ). Results Disability significantly decreased after five years of anti-TNF therapy (ΔHAQ: -0.78, p 65 years, females, and those with a disease duration of more than 10 years, a higher comorbidity index, greater disease activity and disability at baseline, high titres of rheumatoid factor, and contraindications to combination therapy with traditional DMARDs. Steroids were useful in patients with greater baseline impairment. The patients treated with infliximab had a higher disability index at baseline, but showed greater improvement than those treated with etanercept or adalimumab. The results were confirmed by multivariate analysis. Conclusions The effect of anti-TNF therapy on the disability of patients with long-standing RA is certainly substantial, and the HAQ is a good means of evaluating the efficacy of biological treatment. References Aletaha D, Ward MM. Duration of rheumatoid arthritis influences the degree of functional improvement in clinical trials. Ann Rheum Dis. 2006; 65:227-33. Sokka T, Hakkinen A, Krishnan E, Hannonen P. Similar prediction of mortality by the health assessment questionnaire in patients with rheumatoid arthritis and the general population. Ann Rheum Dis. 2004; 63:494-7. Lloyd S, Bujkiewicz S, Wailoo AJ, Sutton AJ, Scott D. The effectiveness of anti-TNF-a therapies when used sequentially in rheumatoid arthritis patients: a systematic review and meta-analysis. Rheumatology 2010; 49:2313–21. Disclosure of Interest None Declared