FRI0506 EFFICACY AND SAFETY OF CANAKINUMAB IN ADULT-ONSET STILL'S DISEASE: A SINGLE-CENTER REAL-LIFE EXPERIENCE

Background:The pro-inflammatory cytokine interleukin (IL)-1 has a central role in the pathogenesis of adult-onset Still's disease (AOSD), a rare auto-inflammatory condition. Anakinra, has been for years the cornerstone of IL-1-blocking therapy in AOSD. More recently, the monoclonal antibody canakinumab, a new agent blocking IL-1, has become availableObjectives:To describe our real-life experience with CNK in a cohort of AOSD patients from a single Italian CenterMethods:AOSD patients diagnosed according to Yamaguchi's criteria followed-up at our Autoinflammatory Unit and treated with CNK for at least 3 months were included. Demographic features, disease characteristics, reasons for CNK introduction, concomitant therapies, variation in systemic steroids dose, adverse events, and response to treatment were retrospectively evaluated. Non-parametric tests were used for statistical comparisonResults:13 patients (5 women; median age 49 years, range 21-74), treated with subcutaneous CNK 4 mg/kg 4-weekly, were identified. Median disease duration before CNK introduction was 12 (6-240) months. After CNK introduction, 2 patients were followed-up for 18 months, 3 for 12 months, 6 for 6 months, 2 for 3 months. CNK was introduced as first-line biologic DMARD in 6 patients. The other 7 patients had been already treated with at least one other bDMARD, for a total of 15 treatment courses (7, anakinra, ANK; 4, tocilizumab; 4, TNF-inhibitors), with a median bDMARD therapy duration of 8 (4-178) months. Previous bDMARDs had been interrupted because of inefficacy (8 cases) or adverse events (AE, 7 cases); of the 7 ANK-treated patients, therapy interruption was due to inefficacy in 3 cases. At CNK introduction, 11 patients were on systemic steroid therapy, prednisone (PDN) equivalent dose 15 (5-80) mg, and 10 were concomitantly receiving a conventional DMARD (7, methotrexate; 2, colchicine; 1, cyclosporine-A).Graphic 1summarizes main clinical features at CNK introduction. After CNK start, a striking and rapid clinical response was observed, as demonstrated by a substantial decrease of modified Pouchot score and a normalization of acute phase reactants after only 3 months (see Table 1 for details). CNK showed also a significant steroid-sparing effect: median PDN dose was reduced to 7.5 (2.5-12.5) mg at month 3 and 5 (0-7.5) mg at month 6; PDN was stopped in 3 patients (1 at month 3, 1 at month 6, 1 at month 12) due to optimal disease control. CNK was temporarily held-off in 3 patients (zoster reactivation, 1; prostatitis, 1; mild leukopenia, 1). We observed no case of primary inefficacyTable 1.Disease activity and blood tests at canakinumab introduction and during follow-upDaily prednisone dosemgBaseline(n=13)3 months(n=13)6 months(n=11)12 months(n=5)18 months(n=2)Pouchot score15 (5-80)7.5 (2.5-12.5)5 (0-7.5)5 (0-7.5)2.5VAS pain3 (2-5)1 (0-2)0 (0-1)00Erythrocyte sedimentation ratemm/h7 (2-10)3 (1-8)2 (1-4)1 (1-2)1C-reactive proteinmg/L42 (8-120)21 (2-69)13 (2-55)14 (2-41)11Ferritinng/mL20.8 (3-180)3.1 (0.5-22.5)1.6 (0.5-8.4)1 (0.3-6.3)0.5Hemoglobing/dL379.5 (161-914)282 (82-552)215 (34-464)177 (77-401)19913.1 (9.4-15.7)13.2 (10.7-15.3)13.8 (11.5-15.5)13.9 (11.3-14.3)13.5Figure 1.Graphic 1 Main clinical features at canakinumab introductionConclusion:Our real-life data confirm that CNK is highly effective and safe in AOSD treatment and has significant steroid-sparing effects. CNK showed its efficacy both as first-line therapy and after other bDMARDs failure, also in patients who have previously failed IL-1 inhibition through ANKReferences:[1] Cavalli G, et al. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology (2015)[2] Cavalli G, et al. Efficacy of Canakinumab as First-Line Biologic Agent in Adult-Onset Still's Disease. Arthritis Res Ther (2019)Disclosure of Interests:Alessandro Tomelleri: None declared, Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Giacomo De Luca Speakers bureau: SOBI, Novartis, Celgene, Pfizer, MSD, Nicola Farina: None declared, Elena Baldissera Speakers bureau: Novartis, Pfizer, Roche, Alpha Sigma, Sanofi, Giulio Cavalli Speakers bureau: SOBI, Novartis, Pfizer, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOB

Classification of schizophrenia using feature-based morphometry

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Bortezomib-induced muscle toxicity in multiple myeloma

Multiple myeloma (MM) accounts for ~13% of all hematologic malignancies. Bortezomib treatment is effective in MM, but can be complicated with neurological side effects. We describe a patient with symptomaticMM who had a reversible metabolic myopathy associated with bortezomib administration and pathologically characterized by excessive storage of lipid droplets together with mitochondrial abnormalities. In a single-center prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, 7 developed muscular signs and/or symptoms. The myopathy was characterized by a proximal muscle weakness involving lower limbs and was an early complication. Complete resolution of muscle weakness occurred after treatment discontinuation. Conversely, none of the patients who received a treatment without bortezomib developed muscular symptoms. Experimental studies demonstrate that in primary human myoblasts bortezomib at low concentrations leads to excessive storage of lipid droplets together with structural mitochondrial abnormalities, recapitulating the pathologic findings observed in patient's muscle. Our data suggest that patients treated with bortezomib should be monitored for muscular signs and/or symptoms and muscle weakness should alert the clinician to the possibility of myopathy. Bortezomib-induced metabolic myopathy is a potentially reversible entity with important implications for management and treatment of patients with MM

Deciphering the components of regional net ecosystem fluxes following a bottom-up approach for the Iberian Peninsula

Quantification of ecosystem carbon pools is a fundamental requirement for estimating carbon fluxes and for addressing the dynamics and responses of the terrestrial carbon cycle to environmental drivers. The initial estimates of carbon pools in terrestrial carbon cycle models often rely on the ecosystem steady state assumption, leading to initial equilibrium conditions. In this study, we investigate how trends and inter-annual variability of net ecosystem fluxes are affected by initial non-steady state conditions. Further, we examine how modeled ecosystem responses induced exclusively by the model drivers can be separated from the initial conditions. For this, the Carnegie-Ames-Stanford Approach (CASA) model is optimized at set of European eddy covariance sites, which support the parameterization of regional simulations of ecosystem fluxes for the Iberian Peninsula, between 1982 and 2006. <br><br> The presented analysis stands on a credible model performance for a set of sites, that represent generally well the plant functional types and selected descriptors of climate and phenology present in the Iberian region – except for a limited Northwestern area. The effects of initial conditions on inter-annual variability and on trends, results mostly from the recovery of pools to equilibrium conditions; which control most of the inter-annual variability (IAV) and both the magnitude and sign of most of the trends. However, by removing the time series of pure model recovery from the time series of the overall fluxes, we are able to retrieve estimates of inter-annual variability and trends in net ecosystem fluxes that are quasi-independent from the initial conditions. This approach reduced the sensitivity of the net fluxes to initial conditions from 47% and 174% to −3% and 7%, for strong initial sink and source conditions, respectively. <br><br> With the aim to identify and improve understanding of the component fluxes that drive the observed trends, the net ecosystem production (NEP) trends are decomposed into net primary production (NPP) and heterotrophic respiration (<i>R</i><sub>H</sub>) trends. The majority (~97%) of the positive trends in NEP is observed in regions where both NPP and <i>R</i><sub>H</sub> fluxes show significant increases, although the magnitude of NPP trends is higher. Analogously, ~83% of the negative trends in NEP are also associated with negative trends in NPP. The spatial patterns of NPP trends are mainly explained by the trends in <i>f</i>APAR (<i>r</i>=0.79) and are only marginally explained by trends in temperature and water stress scalars (<i>r</i>=0.10 and <i>r</i>=0.25, respectively). Further, we observe the significant role of substrate availability (<i>r</i>=0.25) and temperature (<i>r</i>=0.23) in explaining the spatial patterns of trends in <i>R</i><sub>H</sub>. These results highlight the role of primary production in driving ecosystem fluxes. <br><br> Overall, our study illustrates an approach for removing the confounding effects of initial conditions and emphasizes the need to decompose the ecosystem fluxes into its components and drivers for more mechanistic interpretations of modeling results. We expect that our results are not only specific for the CASA model since it incorporates concepts of ecosystem functioning and modeling assumptions common to biogeochemical models. A direct implication of these results is the ability of this approach to detect climate and phenology induced trends regardless of the initial conditions

Increased salience of gains versus decreased associative learning differentiate bipolar disorder from schizophrenia during incentive decision making

Background Abnormalities in incentive decision making, typically assessed using the Iowa Gambling Task (IGT), have been reported in both schizophrenia (SZ) and bipolar disorder (BD). We applied the Expectancy-Valence (E-V) model to determine whether motivational, cognitive and response selection component processes of IGT performance are differentially affected in SZ and BD. Method Performance on the IGT was assessed in 280 individuals comprising 70 remitted patients with SZ, 70 remitted patients with BD and 140 age-, sex-and IQ-matched healthy individuals. Based on the E-V model, we extracted three parameters, 'attention to gains or loses', 'expectancy learning' and 'response consistency', that respectively reflect motivational, cognitive and response selection influences on IGT performance. Results Both patient groups underperformed in the IGT compared to healthy individuals. However, the source of these deficits was diagnosis specific. Associative learning underlying the representation of expectancies was disrupted in SZ whereas BD was associated with increased incentive salience of gains. These findings were not attributable to non-specific effects of sex, IQ, psychopathology or medication. Conclusions Our results point to dissociable processes underlying abnormal incentive decision making in BD and SZ that could potentially be mapped to different neural circuits

Analyzing the causes and spatial pattern of the European 2003 carbon flux anomaly using seven models

Globally, the year 2003 is associated with one of the largest atmospheric CO<sub>2</sub> rises on record. In the same year, Europe experienced an anomalously strong flux of CO<sub>2</sub> from the land to the atmosphere associated with an exceptionally dry and hot summer in Western and Central Europe. In this study we analyze the magnitude of this carbon flux anomaly and key driving ecosystem processes using simulations of seven terrestrial ecosystem models of different complexity and types (process-oriented and diagnostic). We address the following questions: (1) how large were deviations in the net European carbon flux in 2003 relative to a short-term baseline (1998–2002) and to longer-term variations in annual fluxes (1980 to 2005), (2) which European regions exhibited the largest changes in carbon fluxes during the growing season 2003, and (3) which ecosystem processes controlled the carbon balance anomaly . <br><br> In most models the prominence of 2003 anomaly in carbon fluxes declined with lengthening of the reference period from one year to 16 years. The 2003 anomaly for annual net carbon fluxes ranged between 0.35 and –0.63 Pg C for a reference period of one year and between 0.17 and –0.37 Pg C for a reference period of 16 years for the whole Europe. <br><br> In Western and Central Europe, the anomaly in simulated net ecosystem productivity (NEP) over the growing season in 2003 was outside the 1σ variance bound of the carbon flux anomalies for 1980–2005 in all models. The estimated anomaly in net carbon flux ranged between –42 and –158 Tg C for Western Europe and between 24 and –129 Tg C for Central Europe depending on the model used. All models responded to a dipole pattern of the climate anomaly in 2003. In Western and Central Europe NEP was reduced due to heat and drought. In contrast, lower than normal temperatures and higher air humidity decreased NEP over Northeastern Europe. While models agree on the sign of changes in simulated NEP and gross primary productivity in 2003 over Western and Central Europe, models diverge in the estimates of anomalies in ecosystem respiration. Except for two process models which simulate respiration increase, most models simulated a decrease in ecosystem respiration in 2003. The diagnostic models showed a weaker decrease in ecosystem respiration than the process-oriented models. Based on the multi-model simulations we estimated the total carbon flux anomaly over the 2003 growing season in Europe to range between –0.02 and –0.27 Pg C relative to the net carbon flux in 1998–2002