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The pro-algesic transient receptor potential ankyrin 1 (TRPA1) channel, expressed by a subpopulation of primary sensory neurons, has been implicated in various pain models in mice. However, evidence in rats indicates that TRPA1 conveys nociceptive signals elicited by channel activators, but not those associated with tissue inflammation or nerve injury. Here, in rats, we explored the TRPA1 role in mechanical allodynia associated with stimulation of peptidergic primary sensory neurons (neurogenic inflammation) and moderate (partial sciatic nerve ligation, pSNL) or severe (chronic constriction injury, CCI) sciatic nerve injury.Acute nociception and mechanical hypersensitivity associated with neurogenic inflammation and sciatic nerve injury (pSNL and CCI) were investigated in rats with TRPA1 pharmacological antagonism or genetic silencing. TRPA1 presence and function were analysed in cultured rat Schwann cells.Hind paw mechanical allodynia (HPMA), but not acute nociception, evoked by local injection of capsaicin or allyl isothiocyanate, the TRP vanilloid 1 (TRPV1) or the TRPA1 activators was mediated by CGRP released from peripheral sensory nerve terminals. CGRP-evoked HPMA was sustained by a ROS-dependent TRPA1 activation, probably in Schwann cells. HPMA evoked by pSNL, but not that evoked by CCI, was mediated by ROS and TRPA1 without the involvement of CGRP.As found in mice, TRPA1 mediates mechanical allodynia associated with neurogenic inflammation and moderate nerve injury in rats. The channel contribution to mechanical hypersensitivity is a common feature in rodents and might be explored in humans.

In the context of drug-receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination of Hamiltonian replica exchange (HREM) and a novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, and efficiency with respect to the standard nonequilibrium approaches. The method has been applied for the determination of absolute binding free energies of 16 newly designed noncovalent ligands of the main protease (3CLpro) of SARS-CoV-2. The core structures of 3CLpro ligands were previously identified using a multimodal structure-based ligand design in combination with docking techniques. The calculated binding free energies for four additional ligands with known activity (either for SARS-CoV or SARS-CoV-2 main protease) are also reported. The nature of binding in the 3CLpro active site and the involved residues besides the CYS-HYS catalytic dyad have been thoroughly characterized by enhanced sampling simulations of the bound state. We have identified several noncongeneric compounds with predicted low micromolar activity for 3CLpro inhibition, which may constitute possible lead compounds for the development of antiviral agents in Covid-19 treatment.

The European industry sector is responsible for about one-third of the EU's total energy consumption and process-related Greenhouse Gas emissions, which makes it a central factor in the EU's climate and energy strategies. Energy cooperation, i.e., the mutualised generation, use and/or acquisition of energy by at least two companies, has the potential of significantly supporting the successful achievement of these strategies. This paper presents a concept for moving from a single-company sustainable energy intervention approach to cooperative sustainable energy solutions within the framework of industrial parks. Technical, economic, regulatory, organizational, and social barriers for energy-efficient park design and operation on all levels and instruments to overcome them have been systematically analysed, taking correlation of solutions, and park-specific requirements into account, thus providing a holistic workflow. First results show that technical and economic attractiveness, and an enabling legal and policy context, are not always enough. For promising energy cooperation solutions to flourish, cultural, organizational, social, and behavioural factors also play a significant role. Furthermore, findings show that external facilitators are helpful to pool efforts to achieve greater engagement.

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody-drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.

To achieve high performance and high energy efficiency on near-future exascale computing systems, three key technology gaps needs to be bridged. These gaps include: energy efficiency and thermal control; extreme computation efficiency via HW acceleration and new arithmetics; methods and tools for seamless integration of reconfigurable accelerators in heterogeneous HPC multi-node platforms. TEXTAROSSA aims at tackling this gap through a co-design approach to heterogeneous HPC solutions, supported by the integration and extension of HW and SW IPs, programming models and tools derived from European research. This work is supported by the TEXTAROSSA project G.A. n.956831, as part of the EuroHPC initiative. Peer Reviewed Article signat per 51 autors/es: Giovanni Agosta, Daniele Cattaneo, William Fornaciari, Andrea Galimberti, Giuseppe Massari, Federico Reghenzani, Federico Terraneo, Davide Zoni, Carlo Brandolese (DEIB – Politecnico di Milano, Italy, name.surname@polimi.it) | Massimo Celino, Francesco Iannone, Paolo Palazzari, Giuseppe Zummo (ENEA, Italy, name.surname@enea.it) | Massimo Bernaschi, Pasqua D’Ambra (Istituto per le Applicazioni del Calcolo (IAC) - CNR, Italy, name.surname@cnr.it) | Sergio Saponara, Marco Danelutto, Massimo Torquati (University of Pisa, Italy, name.surname@unipi.it) | Marco Aldinucci, Yasir Arfat, Barbara Cantalupo, Iacopo Colonnelli, Roberto Esposito, Alberto R. Martinelli, Gianluca Mittone (University of Torino, Italy, name.surname@unito.it) | Olivier Beaumont, Berenger Bramas, Lionel Eyraud-Dubois, Brice Goglin, Abdou Guermouche, Raymond Namyst, Samuel Thibault (Inria - France, name.surname@inria.fr) | Antonio Filgueras, Miquel Vidal, Carlos Alvarez, Xavier Martorell (BSC - Spain, name.surname@bsc.es) | Ariel Oleksiak, Michal Kulczewski (PSNC, Poland, ariel@man.poznan.pl, kulka@man.poznan.pl) | Alessandro Lonardo, Piero Vicini, Francesca Lo Cicero, Francesco Simula, Andrea Biagioni, Paolo Cretaro, Ottorino Frezza, Pier Stanislao Paolucci, Matteo Turisini (INFN Sezione di Roma - Italy, name.surname@roma1.infn.it) | Francesco Giacomini (INFN CNAF - Italy, name.surname@cnaf.infn.it) | Tommaso Boccali (INFN Sezione di Pisa - Italy, name.surname@pi.infn.it) | Simone Montangero (University of Padova and INFN Sezione di Padova - Italy, name.surname@pd.infn.it) | Roberto Ammendola (INFN Sezione di Roma Tor Vergata - Italy, name.surname@roma2.infn.it)

BackgroundDenosumab is a monoclonal antibody used in patients with osteoporosis. It inhibits the receptor activator NF-kB ligand (RANKL), an essential cytokine mediator of osteoclastogenesis. Some concerns have been raised about Denosumab safety profile, especially when it is administered concurrently with biologic drugs for rheumatoid arthritis (RA) (1,2). Indeed, RANK and RANKL have a known immunomodulatory effect (2). In a retrospective study, Lau et al. (1) showed that patients concurrently treated with Denosumab and biologic disease modifying anti-rheumatic drugs (bDMARDs) had a higher rate of serious infections compared to patients taking bDMARDs only, but no adjustment was made for any observed imbalances in potential confounders, such as age and disease activity, between the groups.ObjectivesThis study aims to evaluate, in a monocentric cohort of RA patients concurrently treated with bDMARDs and Denosumab, the safety of such combination.MethodsWe retrospectively observed RA patients on bDMARDs ± methotrexate and denosumab (DEN group) for comorbid osteoporosis and RA patients treated with bDMARDs±methotrexate (noDEN group) who started treatment in a tertiary care centre from 2015 to 2020. Clinical characteristics were gathered at baseline and at 12-month follow up. We also recorded the occurrence of serious infections between groups (defined as infections requiring hospitalization and/or parenteral antibiotics). We deployed the nearest-neighbour matching algorithm (1:4), based on Propensity Score (PS), in order to adjust for non-randomization. The McNemar’s test was used to compare the frequency of serious infection in the two groups.ResultsDEN group consisted of 36 patients were recruited, while the cohort of patients in noDEN group consisted of 547 individuals (Table 1). After PS matching only 58 patients were noDEN group, matched for disease duration, presence/absence of ACPA antibodies, baseline BMI, baseline DAS28 and daily prednisone dosage. In the matched cohort, we found an increase in terms of frequency of serious infections in DEN group, even if not statistically significant (Figure 1). All the infections were completely resolved after hospitalization and/or parenteral antibiotic treatment, without fatal events or irreversible complications. Both groups were not stratified for bDMARDs mechanism of action (MoA). Of note, in the DEN group Rituximab therapy was admnistered in 22% of patients, while in noDEN group in 12% of them.Table 1.Patients’ characteristics at baseline.Av. Obs.bDMARDs OnlyAv. Obs.bDMARDs + DenosumabFemale, n (%)547466 (85.2%)3834 (89.4%)Age, y (mean±sd)54753.3±13.23863.4±11.1Disease duration, m (mean±sd)472120.2±105.338207.9±126.5DAS28, n(mean±sd)5324.55±1.39382.90±1.44PCR, mg/dL (mean±sd)5391.77±4.51380.81±1.22HAQ, n (mean±sd)5161.28±0.86381.54±0.87ACPA, n. (%)541416 (76.8%)3817 (44.7%)Figure 1.Occurrence of serious infections at 12-months follow-up.ConclusionThe occurrence of serious infections among RA patients receiving denosumab in combination with bDMARDs ± MTX for RA was not significantly increased compared to those receiving bDMARDs ± MTX alone at 12 months from treatment baseline. Further studies powered for detecting difference between bDMARDs MoA are necessary in order to assess the infection risk of denosumab co-administration.References[1]Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting. J Rheumatol. 2018 Feb;45(2):170-176. doi: 10.3899/jrheum.161270. Epub 2017 Nov 15.[2]Is denosumab associated with an increased risk for infection in patients with low bone mineral density? A systematic review and meta-analysis of randomized controlled trials. Int J Rheum Dis. 2021 Jul;24(7):869-879. doi: 10.1111/1756-185X.14101. Epub 2021 Apr 1.Disclosure of InterestsNone declared

BackgroundIn axial spondyloarthritis (axSpA), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a key patient-reported outcome. However, one or more of its components may be missing when recorded in clinical practice.ObjectivesTo determine whether an individual patient’s BASDAI at a given timepoint can be reliably calculated with different single imputation techniques and to explore the impact of the number of missing components and/or differences between missingness of individual components.MethodsReal-life data from axSpA patients receiving tumour necrosis factor inhibitors (TNFi) from 13 countries in the European Spondyloarthritis (EuroSpA) Research Collaboration Network were utilized [1]. We studied missingness in BASDAI components based on simulations in a complete dataset, where we applied and expanded the approach of Ramiro et al. [2]. After introducing one or more missing components completely at random, BASDAI was calculated from the available components and with three different single imputation techniques: possible middle value (i.e. 50) of the component and mean and median of the available components. Differences between the observed (original) and calculated scores were assessed and correct classification of patients as having BASDAIResultsA total of 19,894 axSpA patients with at least one complete BASDAI registration at any timepoint were included. 59,126 complete BASDAI registrations were utilized for the analyses with a mean BASDAI of 38.5 (standard deviation 25.9). Calculating BASDAI from the available components and imputing with mean or median showed similar levels of agreement (Table 1). When allowing one missing component, >90% had a difference of ≤6.9 mm between the original and calculated scores and >95% were correctly classified as BASDAI90% (Figure 1, upper panels). As expected, it was observed that regardless of the BASDAI component set to missing and the imputation technique used, correct classification of patients as BASDAITable 1.Level of agreement between the original and calculated BASDAI and correct classification for BASDAILevel of agreement with Dif≤6.9 mm* (%)Correct classification for BASDAI1 missing componentAvailable93.996.9Value 5073.996.3Mean94.296.8Median93.196.82 missing componentsAvailable83.794.8Value 5040.792.8Mean83.594.8Median82.894.73 missing componentsAvailable71.992.6Value 5028.187.3Mean72.292.6Median69.792.2* The levels of agreement with a difference (Dif) of ≤6.9 mm between the original and calculated scores were based on the half of the smallest detectable change. Agreement of >90% was considered as acceptable. ** Correct classification of >95% was considered as acceptable.Figure 1.Level of agreement between the original and calculated BASDAI and correct classification for BASDAIConclusionBASDAI calculation with available components gave similar results to single imputation of missing components with mean or median. Only when missing one of BASDAI components 5 or 6, single imputation techniques can reliably calculate individual BASDAI scores. However, missing any single component value results in misclassification of patients with original BASDAI scores close to 40.References[1]Ørnbjerg et al. (2019). Ann Rheum Dis, 78(11), 1536-1544.[2]Ramiro et al. (2014). Rheumatology, 53(2), 374-376.AcknowledgementsNovartis Pharma AG and IQVIA for supporting the EuroSpA collaboration.Disclosure of InterestsStylianos Georgiadis Grant/research support from: Novartis, Myriam Riek Grant/research support from: Novartis, Christos Polysopoulos Grant/research support from: Novartis, Almut Scherer Grant/research support from: Novartis, Daniela Di Giuseppe: None declared, Gareth T. Jones Speakers bureau: Janssen, Grant/research support from: AbbVie, Pfizer, UCB, Amgen, GSK, Merete Lund Hetland Grant/research support from: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Medac, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, UCB, Grant/research support from: Abbvie, BMS, Merck, Celgene, Novartis, Simon Horskjær Rasmussen Grant/research support from: Novartis, Johan K Wallman Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, Bente Glintborg Grant/research support from: Pfizer, Abbvie, BMS, Anne Gitte Loft Speakers bureau: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Consultant of: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Karel Pavelka Speakers bureau: Pfizer, MSD, BMS, UCB, Amgen, Egis, Roche, AbbVie, Consultant of: Pfizer, MSD, BMS, UCB, Amgen, Egis, Roche, AbbVie, Jakub Zavada Speakers bureau: Abbvie, Elli-Lilly, Sandoz, Novartis, Egis, UCB, Consultant of: Abbvie, Elli-Lilly, Sandoz, Novartis, Egis, UCB, Merih Birlik: None declared, Ayten Yazici Grant/research support from: Roche, Brigitte Michelsen Grant/research support from: Novartis, Eirik kristianslund: None declared, Adrian Ciurea Speakers bureau: AbbVie, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Consultant of: AbbVie, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Michael J. Nissen Speakers bureau: AbbVie, Eli Lilly, Janssens, Novartis, Pfizer, Consultant of: AbbVie, Eli Lilly, Janssens, Novartis, Pfizer, Ana Maria Rodrigues Speakers bureau: Abbvie, Amgen, Consultant of: Abbvie, Amgen, Grant/research support from: Novartis, Pfizer, Amgen, Maria Jose Santos Speakers bureau: Abbvie, AstraZeneca, Lilly, Novartis, Pfizer, Gary Macfarlane Grant/research support from: GSK, Anna-Mari Hokkanen Grant/research support from: MSD, Heikki Relas Speakers bureau: Abbvie, Celgene, Pfizer, UCB, Viatris, Consultant of: Abbvie, Celgene, Pfizer, UCB, Viatris, Catalin Codreanu Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis, Pfizer, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis, Pfizer, Corina Mogosan: None declared, Ziga Rotar Speakers bureau: Abbvie, Novartis, MSD, Medis, Biogen, Eli Lilly, Pfizer, Sanofi, Lek, Janssen, Consultant of: Abbvie, Novartis, MSD, Medis, Biogen, Eli Lilly, Pfizer, Sanofi, Lek, Janssen, Matija Tomsic Speakers bureau: Abbvie, Amgen, Biogen, Eli Lilly, Janssen, Medis, MSD, Novartis, Pfizer, Sanofi, Sandoz-Lek, Consultant of: Abbvie, Amgen, Biogen, Eli Lilly, Janssen, Medis, MSD, Novartis, Pfizer, Sanofi, Sandoz-Lek, Björn Gudbjornsson Speakers bureau: Amgen, Novartis, Consultant of: Amgen, Novartis, Arni Jon Geirsson: None declared, Pasoon Hellamand Grant/research support from: Novartis, Marleen G.H. van de Sande Speakers bureau: Eli Lilly, Novartis, UCB, Janssen, Abbvie, Consultant of: Eli Lilly, Novartis, UCB, Janssen, Abbvie, Grant/research support from: Eli Lilly, Novartis, UCB, Janssen, Abbvie, Isabel Castrejon: None declared, Manuel Pombo-Suarez Consultant of: Abbvie, MSD, Roche, Bruno Frediani: None declared, Florenzo Iannone Speakers bureau: Abbvie, Amgen, AstraZeneca, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Consultant of: Abbvie, Amgen, AstraZeneca, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis

BackgroundThe recently presented “ORAL Surveillance Study” has suggested increased risk of serious adverse events (AEs) with tofacitinib, a JAK-inhibitor (JAKi), compared to a comparator TNF-inhibitor (TNFi). Currently, there is limited real world evidence for the tolerability and safety of JAKi (1).ObjectivesTo assess the safety of JAKi compared to other biologic agents in rheumatoid arthritis (RA) patients in a real-world population, by evaluating treatment discontinuation for AEs.MethodsPooled patient database from 16 national RA registries from across Europe, Québec (Canada), Turkey, and Israel were used. Treatment discontinuation due to AEs by treatment groups, JAKi versus (vs) TNFi and JAKi vs bDMARDs with other modes of action (OMA), were compared as an overall measure of tolerability and safety of JAKi. Standard descriptive statistics were used for baseline characteristics. We plotted unadjusted cumulative incidence, then the cause-specific Cox model was used to account for competing risks, and to obtain association between covariates and the instantaneous hazard rate for AEs. Variables listed in Table 1 were used for adjustment in the fully-adjusted cause-specific Cox model.Table 1.Baseline characteristics of the study populationJAKi1(BARI, FILGO,TOFA,UPA)OMA2(ABA, ANAK, SARI, TOCI)TNFi3(ADA, CERT, ETAN, GOL, INFL)n = 9208n = 16737n = 64533Treatment duration* (yrs)0.7 [0.2, 1.7]1.1 [0.4, 2.8]1.5 [0.5, 3.9]Age57.556.853.2Female (%)81.380.773.2Disease duration (yrs)9.913.110.7Seropositivity (%)78.775.969.8Previous b/tsDMARD (%) 034.030.859.7 120.925.924.3 216.621.710.4 3 or more28.521.55.6Concomitant GC (%)44.650.741.3Concomitant CsDMARD (%) MTX22.622.028.8 MTX + other9.59.713.1 None50.552.543.5 Other17.415.914.7CRP13.2 (24.1)13.3 (25.6)12.3 (24.1)CDAI23.7 (13.8)22.9 (13.5)22.6 (14.0)DAS 284.7 (1.5)4.7 (1.6)4.6 (1.6)HAQ1.2 (0.7)1.2 (0.7)1.1 (0.7)BMI27.1 (5.9)26.8 (5.8)26.8 (5.8)Patients with at least one Comorbidity (%)51.753.949.6csDMARDs = classical synthetic DMARDs, MTX = methotrexate, GC = glucocorticoids, CRP = C-reactive protein, CDAI = Clinical Disease Activity Index, DAS 28 = Disease Activity Score 28, HAQ = Health Assessment Questionnaire, BMI = Body Mass Index, *Treatment duration (median [IQR]) = Last visit date – start date (if treatment is ongoing), treatment stop date – treatment start date (if treatment has stopped). 1BARI (baricitinib; 44.41 %), FILGO (filgotinib; 0.23%), TOFA (tofacitinib; 49.59%), UPA (upadacitinib; 5.78%); 2ABA (abatacept; 39.96%), ANAK (anakinra; 2.64%), SARI (sarilumab; 3.14%), TOCI (tocilizumab; 52.55%); 3ADA (adalimumab; 31.00%), CERT (certolizumab; 8.33%), ETAN (etanercept; 38.83%), GOLI (golimumab; 9.36%), INFL (infliximab; 12.56%)Results90,478 treatment courses were included in the analysis (Table 1). We observed similar crude incidence rate of treatment discontinuation due to AEs between JAKi and TNFi, but less in JAKi vs OMA (Figure 1). The fully adjusted hazard rate of treatment stop for AEs was also similar in JAKi vs TNFi (HR = 1.02 (95% CI 0.92 – 1.13)), and in JAKi vs OMA (HR= 1.08 (95% CI 0.97 – 1.20)). The rate of treatment stop for AEs was higher in women (HR = 1.29 (95% CI 1.21 – 1.37)) and with an increasing number of previous b/tsDMARDs (HR = 1.50; 1.48; 1.68 for 1, 2, and 3 or more previous b/ts DMARDs, respectively).Figure 1.Comparison of cumulative incidence of treatment discontinuation for adverse events in JAKi, TNFi, and OMA groupConclusionAfter adjusting for potential confounders, the rate of treatment discontinuation for AEs was comparable between JAKi and OMA or TNFi. Treatment discontinuation for AEs comprises a wide range of AEs; future analyses will be performed to investigate specific AEs, such as cancer, serious infections or major adverse cardiovascular events.References[1]Ann Rheum Dis 2022. doi: 10.1136/annrheumdis-2021-221915.Disclosure of InterestsEric Nham: None declared, Romain Aymon: None declared, Denis Mongin: None declared, Sytske Anne Bergstra: None declared, Denis Choquette Speakers bureau: DC reports speaker or consultant fees from Abbvie, Amgen, Eli Lilly, Fresenius-Kabi,Pfizer, Novartis, Sandoz, Tevapharm, Consultant of: Stated above, Catalin Codreanu Speakers bureau: CC reports speaker/consulting fees from AbbVie, Amgen, Astra Zeneca, Boehringer Ingelheim, Ewopharma, Lilly, Novartis, Pfizer, Richter, Consultant of: Stated above, Ori Elkayam Consultant of: OE has received consultant and honorary fees from Pfizer, Lilly, Abbvie, Novartis, Jansen, BI, Kimme Hyrich Speakers bureau: KLH has received speaker honoraria from Abbvie, Grant/research support from: KLH has received grant income from Pfizer and BMS, Florenzo Iannone Speakers bureau: FI has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, SOBI, Roche and UCB, Consultant of: Stated above, Nevsun Inanc Speakers bureau: NI has received consultant and speaker/honoraria from Abbvie, Lilly, MSD, Novartis, Pfizer, Roche, Amgen, Celltrion,UCB., Consultant of: Stated above, Lianne Kearsley-Fleet: None declared, Eirik kristianslund: None declared, Tore K. Kvien Speakers bureau: TKK has received fees for speaking and/or consulting from several companies among them Pfizer, AbbVie, Lilly and Galapagos/Gilead, Consultant of: Stated above, Burkhard Leeb Speakers bureau: BFL has received speaker honoraria from Sandoz, Abbvie, Eli-Lilly, Pfizer, Roche, Grünenthal, Biogen, Celgene, Galina Lukina Speakers bureau: GVL has received speaker fees from Abbvie, Lilly, Novartis, MSD, Roche, Pfizer, Dan Nordström Consultant of: DCN has acted as consultant for AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB, Karel Pavelka Speakers bureau: KP has received honoraria for lectures: MSD, Pfizer, Roche, Eli Lilly, Medac, UCB, SOBI, Biogen, Sandoz, Viatris, Manuel Pombo-Suarez Speakers bureau: MPS reports advisor and speaker honoraria from Janssen, Lilly, MSD, Novartis, Sanofi, Consultant of: Stated above, Ziga Rotar Speakers bureau: ZR has received fees for speaking/consulting from several companies among them Pfizer, AbbVie, and Eli Lilly, Consultant of: Stated above, Maria Jose Santos Speakers bureau: MJS has received speaker fees from Abbvie, AstraZeneca, Lilly, Novartis and Pfizer, Delphine Courvoisier: None declared, Kim Lauper Speakers bureau: KL reports speakers fees for Pfizer, Viatris and Celltrion, Consultant of: KL reports consulting fees for Pfizer, Axel Finckh Speakers bureau: AF reports honoraria and consultancies from Pfizer, BMS, MSD, Eli-Lilly, AbbVie, Galapagos, Mylan, UCB, Viatris, Consultant of: Stated above, Grant/research support from: AF reports grants from Pfizer INC, AbbVie, Galapagos, Eli Lilly

BackgroundIn real-life setting, a greater number of elderly rheumatoid arthritis (RA) patients with impaired glomerular filtration rate (GFR) needs treatment with biologic or target synthetic disease-modifying anti-rheumatic drugs (b/tsDMARD) to achieve disease control and reduce NSAIDs intake. Long-term observational data from the real-life on the use of b/tsDMARD in these patients are scarce.ObjectivesThe aim of this study was to evaluate the retention rate of b/tsDMARD in RA patients with impaired GFR in real-life setting.MethodsData of RA patients treated with at least one b/tsDMARD were retrospectively analyzed form the national Italian GISEA registry from January 2016 to December 2021. Estimated-GFR (eGFR) was calculated with the Cockcroft-Gault equation at the time of any b/tsDMARD prescription. For the purpose of this study, patients were divided in two groups, patients with impaired GFR (eGFR ≤60) and patients with normal GFR (eGFR >60). The retention rate was calculated by the Kaplan-Meier method and compared between these two groups by a log-rank test.ResultsThe study population included 2443 treatment-line with b/tsDMARD from 1888 patients (female 80.4%, age 57±12 years, mean baseline CDAI 17±12, FR/ACPA+ 69.5%) who started a new b/tsDMARD. Disease characteristics are shown in Table 1. 288 treatments with b/tsDMARD were started in patients with impaired eGFR and 2155 in patients with normal eGFR. Compared to patients with eGFR >60, patients with eGFR ≤60 showed higher HAQ-DI (1.3±0.8 vs 1±0.8, pConclusionOur data show that impaired eGFR seems to not influence the persistence of b/tsDMARD treatment in RA patients.Disclosure of InterestsNone declared

Pellet injection represents, to date, the most promising option for core fuelling of the EU-DEMO tokamak. Simulations with the HPI2 pellet ablation/deposition code indicate, however, that sufficiently deep fuel deposition requires injection from the High Field Side (HFS) at velocities ≳1 km/s. Two complementary inboard injection schemes are being explored: one makes use of guide tubes with curvature radii ≥6 m in the attempt of preserving pellet integrity at speeds of ˜1 km/s, the other is investigating the feasibility of injecting high-speed (˜3 km/s) pellets along “direct line of sight” (DLS) trajectories, from either the HFS or a vertical port. Options using quasi-vertical DLS paths routed across the upper vertical port have been explored first, as they can be more easily integrated, Unfortunately, the radial position of the available vertical access (≳9 m from the machine axis) turns out to be unfavorable; further simulations with the HPI2 code predict indeed that vertical injection may be effective only if pellets trajectories are well inboard the magnetic axis. High-speed injection through oblique inboard “DLS” paths, not interfering with the Central Solenoid (CS), are instead predicted to yield good performance, provided that the injection location is ≲2.5 m from the equatorial mid-plane. The angular spread of high-speed free-flight pellets, recently measured using an existing facility, turns out to be enclosed within ˜ 0.7°. This scatter cone may require significant cut off volume of the Breeding Blanket (BB). Moreover, DLS in-vessel conical penetrations may increase the neutron flux outside of the bio-shield, and also result in a significant heat load in the cryogenic pellet source. These issues are being investigated, to identify suitable shielding strategies; preliminary results are reported. The suitability of straight guide tubes to reduce the scatter cone, and hence the corresponding open cross section on BB penetration and the neutron streaming, will be explored as a further step. © 2019 Elsevier B.V.

Across mammalian species, patterned activity in neural populations is a prominent feature of developing sensory cortices. Numerous studies have long appreciated the diversity of these patterns, characterizing their differences in spatial and temporal dynamics. In the murine somatosensory cortex, neuronal co-activation is thought to guide the formation of sensory maps and prepare the cortex for sensory processing after birth. While pioneering studies deftly utilized slice electrophysiology and unit recordings to characterize correlated activity, a detailed understanding of the underlying circuits remains poorly understood. More recently, advances in in vivo calcium imaging in awake mouse pups and increasing genetic tractability of neuronal types have allowed unprecedented manipulation of circuit components at select developmental timepoints. These novel approaches have proven fundamental in uncovering the identity of neurons engaged in correlated activity during development. In particular, recent studies have highlighted interneurons as key in refining the spatial extent and temporal progression of patterned activity. Here, we discuss how emergent synchronous activity across the first postnatal weeks is shaped by underlying gamma aminobutyric acid (GABA)ergic contributors in the somatosensory cortex. Further, the importance of participation in specific activity patterns per se for neuronal maturation and perdurance will be of particular highlight in this survey of recent literature. Finally, we underscore how aberrant neuronal synchrony and disrupted inhibitory interneuron activity underlie sensory perturbations in neurodevelopmental disorders, particularly Autism Spectrum Disorders (ASDs), emphasizing the importance of future investigative approaches that incorporate the spatiotemporal features of patterned activity alongside the cellular components to probe disordered circuit assembly.

With the world plagued by the coronavirus pandemic, efficient automated protocols for a reliable in silico estimate of the binding strength of compounds vs SARS-CoV2-related biological targets are urgently needed. The consensus computational pipeline in drug development starts from triaging via docking tools of data-driven generated libraries of compounds followed by Molecular Dynamics (MD) techniques on a subset of the best scoring ligands. In this context, absolute binding free energy determination via MD is a crucial and challenging intermediate step, preceding the drug optimization process, using efficient alchemical MD techniques on strictly congeneric series. Here we describe an alchemical MD technique based on nonequilibrium thermodynamics capable of delivering in few hours on a modern HPC platform reliable estimates of the absolute binding free energies in drug–receptor systems. The methodology can be combined with well established alchemical relative binding free energy calculations providing an automatable workflow for drug optimization starting from a set of chemically distant ligands.

BackgroundBehçet’s Syndrome (BS) is a multisystem recurring inflammatory disorder characterised by a wide spectrum of clinical manifestations, which can vary from limited mucocutaneous lesions up to severe and even life-threatening events.ObjectivesTo evaluate the impact of BS on the patients’ work activity and productivity.MethodsA sub-cohort of 148 patients from the original Behçet’s syndrome Overall Damage Index (BODI) Project study was enrolled. The Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire was administered. Demographics, disease duration, comorbidity, major organ involvement, ongoing therapy, Behçet's Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA), and the BODI were recorded. Multiple regression models were built to investigate the independent effect of BS features on WPAI.ResultsOverall, 97 (65.6%) out of 148 patients who completed the WPAI:GH questionnaire resulted working for pay; 22 out of 97 (27.8%) patients reported missing work in the past week due to their health, accounting for a mean (SD) of 34.4% (17.8) of their working time (absenteeism). The only factor significantly associated with absenteeism in multivariate analysis was the presence of ocular damage, as assessed by the BODI (β 0.255, p = 0.027).Although 93 patients reported that they worked in the previous week, mean 27.3% (30.7) of their actual work productivity was impaired due to their health problem (presenteeism), with only 37 (38.5%) patients reporting no such loss. Factors associated with work impairment were female gender (β 0.319, p = 0.001), higher PtGA (β 0.298, p = 0.002), and an increased BODI score in the last 2 years follow-up (β 0.212 for one-point increased BODI score, p = 0.024).Finally, 99 (66.9%) of the total 148 patients complained of a daily activity impairment, reporting that a mean of 33.3% (30.6) of their regular daily activities had been prevented due to their health problems. Factors significantly associated with patients’ daily activity impairment were younger age at enrolment (β 0.187, p = 0.021), higher BDCAF disease activity (β 0.235, p = 0.002) and fibromyalgia (β 0.324, p = 0.033).ConclusionBS can lead to missing work time and significantly affect both the patient’s work productivity and daily activities. Active disease seems to be one of the major determinants together with a higher burden of damage and the association of some specific comorbidities, such as fibromyalgia.Table 1.WPAI:GH questionnaire resultsVariablesn°Mean (SD)All patients148Patients working for pay97Percent work time missed due to health977.9 (21.7)Percent work time missed due to health (patients with missed time >0) *2234.4 (17.8)Patients who actually worked in the past seven days**93Percent impairment while working due to health9327.3 (30.7)Percent impairment while working due to health (pts with % impairment while working > 0) ***5645.4 (27.2)Percent activity impairment due to health14833.3 (30.6)Percent activity impairment due to health (those with % activity impairment >0)9949.8 (23.9)* Patients working for pay who missed at least on hour of work, 22/97 = 22.7%.** Patients working for pay, but who worked for > 0 hours in the last week = 93/97*** Patients with impairment while working > 0 among patients who actually worked in the previous 7 day = 56/93.Disclosure of InterestsNone declared

BackgroundAlthough novel therapies with biotechnological agents and small molecules may lead to the complete clearing of psoriasis in the vast majority of patients, the latter drugs only allow Psoriatic Arthritis (PsA) disease control in up to 50% of patients (1). In an increasing number of clinical scenarios, machine learning (ML) is emerging as a tool for the implementation of multi-parametric decision algorithms. ML allows to handle complex non-linear relationships between patient attributes that are hard to model with traditional statistical methods, merging them to output a forecast or a probability for a given outcome, enabling personalized medicine (2).ObjectivesWe aimed to develop a ML algorithm capable of predicting the probability of remission in PsA patients on Secukinumab to support clinicians in choosing the optimal treatment strategy.MethodsPatients with classified PsA according to CASPAR criteria undergoing Secukinumab treatment between September 2017 and September 2020 at our tertiary Centre were retrospectively observed.Either at treatment baseline and at 12-month follow up, we retrieved demographic and clinical characteristics, including Body Mass Index (BMI), disease phenotypes, Disease Activity in PsA (DAPSA), Leeds Enthesitis Index (LEI) and Ankylosing Spondylitis Disease Activity Score (ASDAS, on C-Reactive Protein). After a ML variable selection method, based on an eXtreme Gradient Boosting (XGBoost) wrapper, an attribute core set with the least number of predictors was used for implementing n.3 ML algorithms, namely Logistic Regression (LR), Decision Trees (DT) and XGBoost. Each algorithm was trained and validated with 10-fold cross-validation. The performance of each algorithm in both phases was assessed in terms of of accuracy and area under receiver operating characteristic curve (AUROC).ResultsThe dataset consisted of n.121 PsA patients (62/121 female, 51.2%), with mean age (±SD) 52.9±10.1 years and mean disease duration of 5.9 ±10.4 years. Twenty-five of them (20.7%) had axial involvement whereas 88/121 (72.7%) had polyarticular involvement. Psoriasis was present in 84/121 patients (69.4%). At baseline, mean DAPSA was 14.9 ± 9.2, mean HAQ-DI 1.1 ± 0.7, mean LEI 0.6 ± 1, mean ASDAS 2.5 ± 0.8, mean PASI 2 ± 2.9, mean BMI 28.4 ± 4.9 . Secukinumab at 300 mg dose was administered to 79/121 patients (65.3%). At 12 months DAPSA remission was achieved by 24/121 patients (19.8%). Accuracy of LR, DT and XGBoost was of 0.70 ± 0.11, 0.81 ± 0.07 and 0.89 ± 0.05, respectively. Consistently AUROC (Figure 1 Panels ABC) were 0.63 ± 0.2, 0.79 ± 0.2 and 0.93 ± 0.1, respectively. A sample decision tree explaining XGBoost algorithm function has been provided (Figure 1 Panel D). LEI and DAPSA at baseline were shown as the most important attributes for such algorithm (Figure 1 Panel E).Figure 1.ConclusionML can support Rheumatologists in profiling those patients more likely to respond to Secukinumab.References[1]Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol. 2019 Mar;15(3):153-166. doi: 10.1038/s41584-019-0175-0.[2]Venerito V, Angelini O, Cazzato G, Lopalco G, Maiorano E, Cimmino A, Iannone F. A convolutional neural network with transfer learning for automatic discrimination between low and high-grade synovitis: a pilot study. Intern Emerg Med. 2021 Sep;16(6):1457-1465. doi: 10.1007/s11739-020-02583-x. Epub 2021 Jan 2.Disclosure of InterestsVincenzo Venerito Speakers bureau: Abbvie, Paid instructor for: Pfizer, Lilly, Marco Fornaro: None declared, Fabio Cacciapaglia Speakers bureau: Lilly, Abbvie, BMS. Pfizer, Paid instructor for: Lilly, Sabina Tangaro: None declared, Giuseppe Lopalco Speakers bureau: SOBI NOVARTIS BMS ABBVIE, Paid instructor for: PFIZER, Florenzo Iannone Speakers bureau: Abbvie Pfizer UCB BMS Galapagos Novartis Lilly SOBI ROCHE, Paid instructor for: pfizer

BackgroundPreventing accrual of organ damage represents a primary goal in the treatment of Behçet’s Syndrome (BS), as it may result in impairment of other outcomes, including the health-related quality of life (HR-QoL).ObjectivesThe objective of this study was to investigate whether the recent accrual of organ damage, rather than its extent at a single time point, correlate with an impairment of the HR-QoL.MethodsA sub-analysis of data from patients recruited in the longitudinal phase of the BODI Project validation cohort was performed. The HR-QoL and damage were measured by the Short-form 36 questionnaire (SF-36) and the BS Overall Damage Index (BODI), respectively, at the baseline visit and at a follow-up (FU) 24 ±3 months later. Then the possible increase of damage over FU was assessed by calculating the difference between the BODI score (Δ-BODI) in the two visits. Then, the relationship between the Δ-BODI and the individual and summary domains of the SF-36 was analysed by building multivariate regression models, including age, gender, concomitant fibromyalgia and/or depression, current disease activity as assessed by the BDCAF, as confounding variables.ResultsFrom the BODI validation cohort, 147 patients were recruitable for this sub-analysis;73 (49.8%) were males. The mean (SD) age and disease duration at enrolment were, respectively, 46.2 (12.4) and 13.4 (10.1) years. BODI score did not influence the SF-36 domains assessed at the baseline visit. In contrast, a significant correlation was recorded between the Δ-BODI and the following SF-36 domains: physical function (PF) (β -0.158 for 1 unit increase in BODI score, p 0.025), role physical (RP) (β -0.150, p 0.044), general health (GH) (β -0.199, p 0.004), role emotional (RE) (β -0.180, p 0.001), mental health (MH) (β -0.244, p 0.001), and the mental components summary (MCS) (-0.203, p 0.008)(Figure 1). Gender, age, fibromyalgia and disease activity were also confirmed to significantly influence HR-QoL (Table 1).Table 1.Multiple regression for the assessment of the relationship between Δ-BODI and SF-36 domainsΔ-BODIMaleAgeFBMDPRBDCAFPhysical function (PF)-0.158 (p 0.025)0.180 (p 0.010)-0.299 (p-0.358 (p-- (p 0.552)-0.141 (p 0.044)Role-physical (RP)-0.150 (p 0.044)0.154 (p 0.039)-0.212 (p 0.001)-0.278 (p-- (0.086)-0.251 (pBody-pain (BP)-- 0.8680.266 (p-0.286 (p-0.276 (p-- (p 0.799)-262 (pGeneral health (GH)-0.199 (p 0.004)0.187 (p 0.010)-- (0.136)-0.296 (p-- (0.861)-0.352 (pVitality (VT)-- (p 0.868)0.238 (p 0.001)-0.178 (p 0.008)-0.213 (0.002)-- (p 0.855)-0.371 (pSocial function (SF)-- (p 0.239)0.299 (p 0.004)-0.166 (p 0.024)-0.242 (p 0.001)-- (0.831)-0.202 (p 0.010)Role emotional (RE)-0.180 0.003)0.158 (p 0.047)-0.157 (p 0.048)-0.233 (p 0.003)-- (0.531)-0.191 (p 0.016)Mental health (MH)-0.244 (p 0.001)-- (p 0.142)-- (p 0.142)-0.292 (p-- (p 0.073)-0.254 (p 0.001)Physical Component Summary (PCS)-- 0.1050.229 (p 0.001)-0.298 (p-0.296 (p-0.254 (pMental Component Summary (MCS)-0.203 (p 0.008)-- (p 0.068)-- (0.246)-0.255 (p 0.001)-- (0.122)-0.302 (pFBM: fibromyalgia; DPR: depressionConclusionThe recent accrual of organ damage, rather than its extent assessed in a single visit, is associated with impairment of different aspects of heath related quality of life, especially those mental related. Such phenomenon is similar to that observed in other systemic rheumatic disease, may be due to coping mechanisms.Disclosure of InterestsNone declared

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategies to curb the coronavirus disease-19 (COVID-19) pandemic. Despite the mass-scale vaccination, literature data about the incidence of disease flares in IIM patients are still not reported as well as the immunological condition.ObjectivesThe present study aimed to describe the clinical status of patients affected by IIM after vaccination against COVID19 in order to assess the number of relapses or immune-mediated reactions in a cohort of Italian patients with such disease.MethodsWe included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. Inclusion criteria were a recent (ResultsA total of 119 IIM patients (median, IQR 58 (47-66) years; 32 males) were consecutively enrolled. Fifty had a diagnosis of DM, 39 had PM and 30 had ASS. The median months of disease duration was 79.62±83.98. According to number of organs involvement, forty-two had only one, 45 had two organs involvement, 20 had three, 11 had four and one had five. The majority of them received two doses of COVID-19 vaccine, except four patients who refused the vaccination: 94 (78.9%) Cominarty, 16 (13.4%) Moderna, 5 (0.04%) AZ. Seven (0.06%) patients had flare after vaccination, the majority of them were mild except one major with three organs involved and one life-threatening with systemic involvement. In order to understand or predict the effect of demographic and clinical features on the flare development after vaccination, a logistic regression analysis was performed. The goodness-of-fit statistics showed a Chi2 associated with the Log ratio (L.R.) of 0.045. From the probability associated with the Chi-square tests, the Type II analysis showed the variable that most influences the development of flare was the number of organs involved (p=0.047).Sixty-eight patients received the third dose of COVID-19 vaccination: 51 (75%) Cominarty and 17 (25%) Moderna. Only one (0.01%) patient (the same who had life-threatening flare with systemic involvement after two doses) had flare after third dose and eventually died.ConclusionVaccines against SARS-CoV2 have provided, both in registratory studies and in preliminary real-life evidence, an overall good efficacy and safety. Nevertheless, only scanty data are available for rheumatic patients in general and the ones affected by IIM in particular. To the best of our knowledge, ours represent the largest cohort of IIM patients in which immunogenicity of anti-SARS-CoV2 vaccine was assessed. In line with real-life data from other diseases, we found a non-statistically significant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease.ParametersFlare after two doses (n=7)No-flare after two doses (n=108)P valueAge (years)55 (51-68)59 (47-67)NSGender (M/F)2/530/82NSDiagnosis (DM/PM/ASS)2/2/348/36/28NSAntibodiesJo1225PL7-3PL12-1Ku-2Mi217PM/Scl15Ro5217TIG1g-5MDA5-6SRP-1SAE-2cN1a--NPX-1SSA-12Ds-DNA-1ANA (only positivity)-3negative227Length of disease (months)50 (19-200)60 (24-108)NSNumber of organs involved:One0360.0004Two243Three319Four110Five10Type of vaccination:Cominarty688NSModerna115AZ05Disease activity (PhGA≥2/PhGA3/427/81NSMDI3 (1-6.5)2 (1-4)NSCRP (mg/dL)0.1 (0.01-0.3)0.99 (0.3-2.9)0.0041ESR32 (14-39)15.5 (8-27.5)NSCPK111 (63-905)97.5 (63-158)NSTreatment at time of vaccination: GCs010NS Immunosuppressive319 Biologic12 Combination365 no-treatment-12Disclosure of InterestsNone declared

BackgroundConsidering the highest adverse events risk (predominantly infectious disease and osteoporosis) of glucocorticoids (GCs), EULAR recommended a short-term use of GCs with rapid tapering as soon as clinically feasible in rheumatoid arthritis (RA) patients. Although a prednisone dose less than or equal to 7,5 mg/die is considered more safety, the complete discontinuation of the GCs would be desirable. Few data are available on real tapering or withdrawal of GCs in RA patients treated with DMARDs both in clinical trial and registry study.ObjectivesTo evaluate the steroid tapering rate and the discontinuation of GCs in RA patients treated with biological-DMARDs (b-DMARDs) or target synthetic DMARDs (ts-DMARDs) in different treatment lines.MethodsWe revised retrospectively 1616 clinical records of RA patients who started b/ts-DMARDs between December 2017 and June 2021. We recruited 420 RA patients who were stably treated for at least 6 months with b/ts-DMARDs with or without cs-DMARDs and were taken GCs at baseline visit. The evaluations of GCs discontinuation time were realized by Kaplan-Meier estimate, followed by log-rank (Mentel-Cox) test for the comparison among different b/ts-DMARDs groups. Statistical significance was set at p ⩽ 0.05.ResultsRA patients treated with different b/ts-DMARDs were comparable for disease duration (anti TNF-alpha: 76 weeks ± 64; JAK-I: 121 weeks ± 122; anti-IL6: 78 weeks ± 70; abatacept: 111 weeks ± 121), disease activity (DAS 28 ESR: anti TNF alpha: 3,9 ± 1,3; JAK-I: 4,1 ± 1; anti IL-6: 4 ± 1,3; abatacept: 4 ± 1,2; p=0,958), and GCs dose (anti TNF alpha: 5,7 mg ± 7,5; JAK-I 5,5 mg ± 2,5; anti IL-6 5,7 mg ± 4,1; abatacept 5,6 mg ± 2,5; p=0,879) at baseline visit. 158 RA patients started for the first-time b/ts-DMARDs, 83 patients started 2nd line of b/ts-DMARDs, 66 patients started 3rd line b/ts-DMARDs and 113 patients were failure to more than 3 b/ts-DMARDs.Considering RA patients who started b/ts-DMARDs for the first time, the groups treated with anti-IL6 or JAK-I showed a shorter discontinuation time than those treated with anti TNF-alpha or Abatacept (respectively 22 weeks ± 0,7, 22,6 weeks ± 0,7, 23,8 weeks ± 0,1, 23,1 weeks ± 0,4; p=0,046). As regards the steroid sparing in 6th month of follow-up, the rates of GCs dose spared than the staring GCs dose were higher in JAK-I (44%) and anti-IL 6 (42%) compared to abatacept (30%) and anti-TNF alpha (33%).Considering the group of RA patients treated in 2nd or other lines of b/ts-DMARDs, no differences were found among various treatments in GCs discontinuation time.ConclusionIn clinical practice GCs are useful therapeutic tools to reach as rapidly as possible low disease activity in RA patients; but the possible adverse effects of long-term GCs treatment limit their use. The introduction of biotechnological drugs has significantly improved clinical management of RA patients, achieving the aim of rapid GCs discontinuation or their dose reduction. In particular, the mechanisms of action of anti-IL6 and JAK-I seems perform more quickly on steroid discontinuation than anti TNF alpha or abatacept, above all in 1st line of b/ts-DMARDs in RA patients.Disclosure of InterestsNone declared

BackgroundRituximab (RTX) is an effective remission-induction treatment in ANCA-associated vasculitides (AAVs). Some reports have suggested that it might be effective also in Eosinophilic Granulomatosis with Polyangiitis (EGPA), to induce and maintain remission of vasculitic manifestations [1,2]. However, its effects for preventing respiratory relapses seem to be poor. Mepolizumab (Mepo) (both 100 and 300mg/month) is effective in improving respiratory manifestations and lung function, while partially controlling also systemic activity [3,4]. Isolated case reports further indicate that the sequential therapy with RTX and Mepo might be effective [5-7].ObjectivesThe study aimed to investigate the efficacy and safety of a therapeutic regimen based on sequential RTX and Mepo for the control of EGPA.MethodsA multicenter, retrospective, cohort study was conducted on adult patients diagnosed with EGPA according to the ACR classification criteria [8] or MIRRA trial criteria [3]. Only patients who received induction therapy with RTX (any dosage), and subsequent treatment with Mepo (100-300 mg/4 weeks) within 12 months from last RTX administration were included. Patients receiving other induction therapies between RTX and Mepo were excluded. The effectiveness of sequential RTX and Mepo was assessed in terms of disease activity (by the Birmingham Vasculitis Activity Score, BVAS) and daily corticosteroid dosage. Safety data were also collected.ResultsThirty-four EGPA patients treated with sequential RTX and Mepo were included (59% females, median age of 51 years (IQR 40-58); 41% ANCA positive).In most cases (26/34; 76%), RTX was started at the dosage of 1g q2w, and all except two patients had active disease at time of RTX beginning [median BVAS of 9 (IQR 6-14)]. Specifically, most patients started RTX for the control of systemic manifestations (19/34; 56%), or of both systemic and respiratory symptoms (11/34; 32%). All except one patient were receiving oral corticosteroids, at a median dosage of 25 mg/day (10-38).Mepo was started after a median of 14 months (6-23) from RTX initiation and after a median of 5 months (IQR 3-11) from the last RTX administration. Mepo was used at the dosage of 100mg/4 weeks in 32/34 (94%), mostly for the control of respiratory manifestations (25/34, 74%). At the time of starting Mepo, the median BVAS was 4 (2-8), and median prednisolone dose 10 mg/day (7-15). After a median follow-up of 28 months (IQR 23-33) from starting Mepo, the median BVAS decreased to 1.5 (IQR 0-4) and the median corticosteroid dosage to 5 mg/day (2.5-5), with 7/34 (21%) patients being off steroids. At last follow-up, most patients were off-RTX (28/34), typically due to stable disease remission (20/34; 59%).Both RTX and Mepo were well-tolerated; 5 patients had adverse events on RTX (none serious), and 5 on Mepo (including one serious infection).ConclusionSequential use of RTX and Mepo seems to be effective for remission induction and maintenance in EGPA.References[1]Emmi, Ann Rheum Dis, 2018[2]Teixeira, RMD Open, 2019 3. Wechsler, NEJM, 2017[4]Bettiol, Arthritis Rheumatol, 2021[5]Shiroshita, Respir Med Case Rep, 2018[6]Higashitani, Mod Rheumatol Case Rep, 2021[7]Afiari, Cureus 2020[8]Masi, Arthritis Rheum, 1990Table 1.Effectiveness of sequential RTX and Mepo in the 34 patients included in the studyRTX beginningMepo beginningLast follow-upMedian time elapsed (IQR)-14 months (6-23) from RTX beginning28 months (23-33) from Mepo beginningDosage1g q2w (26/34);100mg/4 weeks (32/34)6 patients off Mepo; 28 patients off RTX375mg/m2 for 4 weeks (8/34)300mg/4 weeks (2/34)Reason for treatment beginning (manifestations)Systemic (19/34);Respiratory (25/34);-Systemic + respiratory (11/34);Systemic (4/34);Only respiratory (3/34);Remission maintenance (5/34)Other (1/34)BVAS (median, IQR)9 (6-14)4 (2-8)1.5 (0-4)Prednisolone dosage (median, IQR), mg/day25 (10-38)10 (7-15)5 (2.5-5)Disclosure of InterestsAlessandra Bettiol: None declared, Maria Letizia Urban: None declared, Federica Bello: None declared, Davide Fiori: None declared, Irene Mattioli: None declared, Giuseppe Lopalco: None declared, Florenzo Iannone: None declared, Allyson Egan: None declared, Luca Moroni: None declared, Lorenzo Dagna Consultant of: Consultation honoraria from GSK outside the current work, Marco Caminati: None declared, Simone Negrini: None declared, Paolo Cameli: None declared, Marco Folci: None declared, Paola Toniati: None declared, Roberto Padoan: None declared, Oliver Flossmann: None declared, Roser Solans-Laqué: None declared, Laura Losappio: None declared, Jan Schroeder Consultant of: Advisory Board fees from AstraZeneca and GSK, Marc André: None declared, Laura Moi: None declared, paola parronchi Consultant of: Consultation honoraria from GSK and Novartis, Fabrizio Conti: None declared, Savino Sciascia: None declared, David Jayne Consultant of: Consultant for Astra-Zeneca, Aurinia, BMS, Boehringer-Ingelheim, Chemocentryx, Chugai, CSL, GSK, Infla-RX, Janssen, Novartis, Roche/Genentech, Takeda and Vifor, Augusto Vaglio Consultant of: Consultation honoraria from GSK outside the current work, Giacomo Emmi Consultant of: Consultation honoraria from GSK outside the current work

BackgroundSystemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by autoimmunity-driven damage and vasculopathy leading to fibrosis of the skin and internal organs (1). The Janus kinase (Jak) - signal transducer and activator of transcription (STAT) pathway has been evidenced markedly activated in SSc patients (2, 3), and its inhibition has been proved in preclinical and clinical trials (4), but no data on Jak selective inhibition are available.ObjectivesTo explore the effect of selective inhibition of Jak/STAT pathway in peripheral blood mononuclear cells (PBMC) from SSc patients.MethodsIn vitro Jak inhibition of the subunit 3 of phosphorylated (p) than activated STAT was measured by flow cytometry in peripheral blood mononuclear cells (PBMC) from SSc patients naïve to any immunosuppressive and/or corticosteroids (n.5). pSTAT3 activity was also assessed after stimulation with recombinant human 0.1 ng/ml IL-6 (Peprotech – NJ, USA). The PBMC were overnight incubated with IC50 concentrations of selective Jak1-, Jak2-, Jak3- and Tyk2-inhibitors (Biovision Inc. – CA, USA). Percentages of pSTAT3 positive cells were compared in presence of different compounds stimulation.ResultsAfter overnight incubation, percentage of pSTAT3 positive cells was significantly higher in CD14pos compared to CD4pos (16.3%; 95CI 10-22 vs 10.7%; 95CI 4--18, – p=0.02). pSTAT3posCD14pos cells were halved only by selective Jak3-inhibitor, while pSTAT3posCD4pos cells were reduced by 36% by selective Jak1-inhibitor. Selective Jak2- or Tyk2-inhibitors did not interfere with STAT3 phosphorylation in PBMC from SSc patients. After IL-6 stimulation, we observed a 2- and a 1.5-fold increase in percentage of pSTAT3posCD4pos and pSTAT3posCD14pos cells, respectively. pSTAT3posCD14pos cells were reduced in the PBMC co-culture with IL-6 and Jak-selective inhibitors, in contrast no effects were found in CD4pos cells. Specifically, selective Jak1- and Jak3-inhibitors reduced pSTAT3posCD14pos cells by an average of 37% and 25%, respectively. No effects were observed after co-culture with IL-6 and selective Jak2- or Tyk2-inhibitors.ConclusionJak/STAT3 pathway of PBMC from SSc patients with active disease may be differently modulated by specific inhibitors. Selectivity of Jak1- and Jak3-inhibitors seems more relevant, especially in CD14pos monocytes after IL-6 stimulation. These preliminary findings highlight some evidence for effectiveness of selective Jak-inhibitors in SSc treatment.References[1]Benfaremo D, et al. Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches. Biomedicines. 2022;10(1):163.[2]Talotta R. The rationale for targeting the JAK/STAT pathway in scleroderma-associated interstitial lung disease. Immunotherapy. 2021;13(3):241-256.[3]Cacciapaglia F, et al. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is highly expressed in CD14+ circulating cells of scleroderma patients. Rheumatology (Oxford). 2020;59(6):1442-1444.[4]Karalilova RV, et al. Tofacitinib in the treatment of skin and musculoskeletal involvement in patients with systemic sclerosis, evaluated by ultrasound. Rheumatol Int. 2021;41(10):1743-1753.Disclosure of InterestsNone declared

BackgroundSubcutaneous (SC) CT-P13 is the first and only subcutaneous formulation of infliximab (IFX) approved by the EMA.1 In the pivotal study (NCT03147248), non-inferiority of SC IFX to intravenous (IV) was demonstrated in rheumatoid arthritis (RA) patients using 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) improvement at Week 22, with a statistically significant treatment difference of 0.27 (95% CI 0.02, 0.52) favoring the SC versus the IV arm.2,3 At Week 30, numerical differences in efficacy outcomes were shown between SC and IV IFX favoring SC IFX. IV group patients switched to SC IFX by Week 30, and the difference between the groups was reduced at Week 54.2ObjectivesTo investigate whether there was a statistically significant difference between SC and IV IFX at Weeks 30 and 54 in the phase 3 pivotal study of CT-P13 SC using conservative missing imputation methods.MethodsPatients with active RA who had an inadequate response to MTX received IV IFX 3mg/kg at Weeks 0 and 2 for induction and were randomized at a 1:1 ratio to receive SC IFX 120mg every 2 weeks or IV 3mg/kg every 8 weeks thereafter for maintenance. Patients who were randomized to receive IV IFX switched to SC at Week 30. In this post-hoc analysis, non-responder imputation (NRI) and last observation carried forward (LOCF) methods were used to investigate whether the difference in efficacy outcomes between SC and IV IFX at Weeks 30 and 54 was statistically significant. Assessments included EULAR (CRP/ESR)/ACR response; remission rate and low disease activity (LDA) rate based on DAS28 (CRP/ESR), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI); Boolean remission rate; and the proportion of patients achieving a minimal clinically important difference (MCID) in Health Assessment Questionnaire (HAQ).ResultsOf the 343 randomized patients, 165 patients who received SC IFX and 174 patients who received IV IFX from the efficacy population were included in the analysis. There was a statistically significant difference in SC IFX compared to IV treated patients at Week 30 using both NRI and LOCF methods in almost all the clinical variables. However, the difference in efficacy outcomes between SC IFX and IV was reduced at Week 54 after the IV group switched to SC. This supports the improved efficacy of SC IFX at Week 30. Some of the key results (EULAR [CRP] responses, LDA rates based on DAS28 [CRP], CDAI, and SDAI) were presented in Figure 1. Analysis using LOCF and NRI methods yielded consistent results across most of the efficacy outcomes.Figure 1.Comparison of clinical outcomes between SC IFX and IV IFX in patients with active rheumatoid arthritis.*PP-value for difference in proportion between SC and IV treatment group was obtained by asymptotic Wald test.Low disease activity based on DAS28 (CRP) (< 3.2), CDAI (eatment group AI (≤ 11.0).ConclusionStatistical analyses using conservative missing imputation methods showed significantly greater improvements in clinical outcomes with SC IFX compared to IV at Week 30 in patients with RA. Between-group differences was reduced at Week 54, suggesting improved responses after switching from IV to SC.References[1]Remsima summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/remsima-epar-product-information_en.pdf. Published 2021. Accessed 10 January 2022.[2]Westhovens R, Wiland P, Zawadzki M, et al. Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial. Rheumatology (Oxford). 2021;60(5):2277-2287.[3]Combe B, Allanore Y, Alten R, et al. Comparative efficacy of subcutaneous (CT-P13) and intravenous infliximab in adult patients with rheumatoid arthritis: a network meta-regression of individual patient data from two randomised trials. Arthritis Res Ther. 2021;23(1):119.Disclosure of InterestsArnaud Constantin Speakers bureau: Abbvie, Amgen, Boehringer, Celltrion, Galapagos, Janssen, Lilly, Novartis, Sanofi, UCB, Consultant of: Abbvie, Amgen, Boehringer, Celltrion, Galapagos, Janssen, Lilly, Novartis, Sanofi, UCB, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Lilly, Pfizer, Fresenius-Kabi, MSD, UCB, Roche,Janssen, Novartis, Sandoz, Consultant of: Abbvie, Amgen, BMS, Celltrion, Galapagos, Lilly, Pfizer, MSD, UCB, Janssen, Novartis, Sandoz, Christopher John Edwards Speakers bureau: Abbvie, Astra Zeneca, Celltrion, Chugai, Fresenius, Galapagos, Gilead, GSK, Lilly, Janssen, Pfizer, Roche, Consultant of: Abbvie, Astra Zeneca, Chugai, Galapagos, Gilead, GSK, Lilly, Janssen, Pfizer, Roche, Grant/research support from: Celltrion, Pfizer, Abbvie, Joao Eurico Fonseca Speakers bureau: Abbvie, Ache, Janssen, Lilly, Medac, Novartis, Pfizer, Consultant of: Abbvie, Celltrion, Janssen, Lilly, Pfizer, Grant/research support from: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Florenzo Iannone Speakers bureau: Abbvie, BMS, Celltrion, Galapagos, MSD, Eli-Lilly, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, BMS, Celltrion, Galapagos, MSD, Eli-Lilly, Janssen, Pfizer, Grant/research support from: BMS, MSD, Edward Keystone Speakers bureau: Amgen, AbbVie, Celltrion, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, Hendrik Schulze-Koops Consultant of: Celltrion, Taeksang Kwon Employee of: Celltrion Healthcare, Seungmin Kim Employee of: Celltrion Healthcare, Sangwook Yoon Employee of: Celltrion Healthcare, Dong-Hyeon Kim Employee of: Celltrion Healthcare, Gahee Park Employee of: Celltrion Inc., DaeHyun Yoo Speakers bureau: Celltrion, Celltrion Healthcare

BackgroundOne of the most intriguing aspects in the management of patients with inflammatory arthritis is the safety of novel therapies in those with a recent history of malignancy or active neoplasm. In this regard, apremilast (APR), an oral PDE4 inhibitor, is emerging as one of the safest therapeutic options in patients with PsA with comorbid cancer.ObjectivesThis retrospective study aims to assess the effectiveness and safety of APR in PsA patients with a recent history of malignancy or active cancer.MethodsWe retrospectively observed patients with a history of neoplasm diagnosed from 1997 to 2021, who underwent apremilast treatment from 2017 to 2021 in a tertiary care centre. We recorded demographic and clinical characteristics at APR baseline and last visit. Furthermore, we recorded the eventual recurrence of primary cancer or the onset of new neoplasms. Paired t-test was used to assess the difference of continuous variables at different follow-ups.ResultsThirteen patients (sex: female 6/13, 46,15%; mean age (mean ± 63,7 years sd ± 9,9 years)) started Apremilast between 2017 to 2021 in a tertiary care center. We assessed their clinical condition using DAPSA, LEI and PASI score in the baseline and in the last visit. Mean follow-up time was 32,02 ± 18,92 months.Mean DAPSA at baseline 20,55 ± 9,15 decreased to 16,21 ± 1,73 at last visit. Similarly mean LEI at baseline was 1,23 ± 1,58 and decreased to 0,61 ± 0,35 at last visit, even in absence of statistical significance (p=0,15). Conversely mean PASI at baseline (1,76 ± 2,57) did not show a decrease (1,61 ± 0,93);Ten patients were still treated with apremilast at last available follow-up. Patient 6 (Table 1) experienced the relapse of Ductal Breast Papilloma. For patient 8, a relapse of primary cancer occurred. Patient 9 had the onset of a new neoplasm. The APR was not discontinued as such malignancies were not considered as treatment associated.Three patients (4, 6, 10) discontinued APR due to intolerance or lack of efficacy.ConclusionAPR seems a safe option in PsA patients with a recent history of malignancy or active cancer, improving articular involvement.Disclosure of InterestsNone declared

BackgroundPatients with autoimmune systemic diseases (ASDs) can be counted among frail populations as regards the predisposition to COVID-19 due to the frequent visceral organ involvement and comorbidities, as well as the ongoing immunomodulating treatments.ObjectivesOur long-term multicenter telephone survey prospectively investigated the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients during the first 3 pandemic waves.MethodsA large series of 3,918 ASD patients (815 M, 3103 F; mean age 59±12SD years) was consecutively recruited at the 36 referral centers of COVID-19 & ASD Italian Study Group. In particular, ASD series encompassed the following conditions: rheumatoid arthritis (n: 981), psoriatic arthritis (n: 471), ankylosing spondylitis (n: 159), systemic sclerosis (n: 1,738), systemic lupus (172), systemic vasculitis (n: 219), and a miscellany of other ASDs (n: 178). The development of COVID-19 was recorded by means of telephone survey using standardized symptom-assessment questionnaire (1).ResultsA significantly increased prevalence of COVID-19 (8.37% vs 6.49%; pInterestingly, a significantly higher COVID-19-related death rate was observed in systemic sclerosis patients compared to the Italian general population (6.29% vs 2.95%; p=0.018). Other adverse prognostic factors to develop COVID-19 were the patients’ older age, male gender, pre-existing ASD-related interstitial lung involvement, and chronic steroid treatment. Conversely, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs 46.99%; p=0.000), as well as the chronic administration of low dose aspirin in a subgroup of SSc patients (with 5.57% vs without 27.84%; p=0.000).ConclusionThe cumulative impact of COVID-19 on ASD patients after the first 3 pandemic waves revealed less severe than that observed during the first phase of pandemic (1), especially with regards to the death rate that was comparable to the Italian general population in spite of the increased prevalence of complicating COVID-19 in the same ASD series.Ongoing long-term treatments, mainly csDMARDs, might usefully contribute to generally positive outcomes of in this frail patients’ population.Of note, a significantly increased COVID-19-related mortality was recorded in only SSc patients’ subgroup, possibly favored by pre-existing lung fibrosis. Among different ASD, SSc deserves special attention, since it shares the main pathological alterations with COVID-19, namely the interstitial lung involvement and the endothelial injury responsible for diffuse microangiopathy.Besides SSc, the patients’ subgroups characterized by older age, chronic steroid treatment, pre-existing interstitial lung disease, and/or impaired COVID-19 vaccine response (1-3), may deserve well-designed prevention and management strategies.References[1]Ferri C, et al. Ann Rheum Dis. 2020 Oct 14 doi: 10.1136/annrheumdis-2020-219113.[2]Ferri C et al. J Autoimmun. 2021 Dec;125:102744. doi: 10.1016/j.jaut.2021.102744.[3]Visentini M et al. Ann Rheum Dis. 2021 Nov 24. doi: 10.1136/annrheumdis-2021-221248Disclosure of InterestsNone declared

BackgroundMuscle involvement is only one feature of idiopathic inflammatory myopathies (IIM). Muscle enzymes do not always represent the best marker of disease activity and other inflammation markers such as ESR and CRP may be normal even with an active disease. Pentraxin-3 (PTX3) is an inflammatory marker produced in many inflammatory and non-inflammatory cells and serum level has been related to higher risk of major cardiovascular events and atherosclerosis1. PTX3 levels have been examined in various rheumatic and autoimmune diseases2, but data of PTX3 levels in patients affected with IIM have not been reported.ObjectivesThe aim of the current study was to identify whether serum PTX3 level could be a marker of disease activity in patients affected with IIM.MethodsTwenty patients affected with IIM (13 Dermatomyositis and 7 Polymyositis), 10 rheumatoid arthritis patients and 10 healthy controls (HC) aged, sex and BMI matched were evaluated. PTX3 levels was assessed using a commercially available enzyme-linked immunosorbent assay (Human Pentraxin3 ELISA Kit, Abcam) kit. Three different cardiovascular risk scores were used to estimate the 10-years CV risk. Carotid intima media thickness (cIMT) was measured with a My Lab XPro80 (Esaote SpA, Genova, Italy) using a linear array ultrasound probe small parts broadband transducer (5–15 MHz) both in right and left carotid. Myositis disease activity was evaluated by using myositis disease activity assessment visual analog scales (MYOACT) [19] established by the International Myositis Assessment and Clinical Studies (IMACS) group. Manual muscle test (MMT8) was used to assess muscle impairment. Exclusion criteria were a diagnosis of diabetes or a history of previous major CV events.ResultsDemographic and disease characteristics of our cohort are showed in Table 1. IIM patients showed higher levels of PTX3 compared to HCs (518±260 pg/ml vs 275±114 pg/ml, pTable 1.IIM 20pz (13 DM, 7 PM)RA 10pzHealthy Control 10pzFemale, n. (%)18 (90%)9 (90%)9 (90%)Age55,3 (7,8)58,3 (5,9)54,6 (6,5)BMI25,5 (4,1)23,9 (3,1)24,6 (3,5)Duration of disease, median (IQR)7,3 (4 – 12,8)13,5 (10,5 – 18,5)*Physician Global Assessment2,1 (2,1)2 (2,2)Patient Global Assessment4 (3,6)2,7 (2,3)Health Assessment Questionnaire0,7 (0,8)0,9 (0,9)Manual Muscle Testing 876,2 (6,6)DAS282,6 (1,1)Skin involvement, n. (%)13 (65)Lung involvement, n. (%)7 (35)Dysphagia, n. (%)11 (55)Arthritis, n. (%)4 (20)Malignancies, n. (%)0 (0)0 (0)0 (0)Arterial hypertension, n. (%)6 (30)2 (20)1 (10)Current steroid therapy2,5 (0 – 5)0 (0 – 3,8)Smoking, n. (%)6 (30)2 (20)3 (30)Total cholesterol, mg/dl203,3 (28,6)215,0 (29,5)216,2 (27,3)HDL cholesterol, mg/dl62,7 (14,7)62,6 (14,2)65,1 (18,2)ESR, mm/h16,7 (12,2)19 (11,7)PCR, mg/l2,9 (2,1)4,1 (5)SCORE median (IQR)0,5 (0 – 2)1 (0 – 3)1 (0,8 – 1,3)CUORE median (IQR)1,9 (0,6 – 3,5)1,6 (1 – 4)1,7 (1,2 – 2,8)QRISK3 median (IQR)4,7 (2,1 – 11,3)7,5 (3,2 – 13,6)4,2 (3,1 – 5,5)QIMT Max, median (IQR)742,5 (636,8 – 804)833 (685,3 – 961) *756 (711 – 820)Mean QIMT, median (IQR)679 (613,1 – 736,3)764,3 (664,5 – 854,1) *703,3 (697,3 – 742,8)Pentraxin 3, pg/ml518 (260)383 (146)275 (114)*Data are expressed as “mean (SD)” where not otherwise specified.*pConclusionIn IIM patients, PTX3 levels are higher than HC and correlate with disease activity, both for muscular and extra-muscular manifestations, being a possible biomarkers of disease activity.References[1]Front Immunol. 2019; 10: 823[2]Arch Med Sci. 2020; 16(1): 81–86Disclosure of InterestsNone declared

BackgroundJuvenile systemic sclerosis (jSSc) is an orphan autoimmune disease with a prevalence of 3 in 1 000 000 children. Information on long-term development of organ involvement and clinical characteristics of jSSc patients in adulthood are lacking. It was believed that patients in adult cohorts may represent a survival biased population.ObjectivesTo assess differences in clinical characteristics of jSSc-onset patients from the pediatric age group, with a mean disease duration of 3 years, compared to the adult age jSSc-onset group, with a mean disease duration of 18.5 years.MethodsWe extracted clinical data at time of inclusion into the cohorts from the Juvenile Scleroderma Inception Cohort (jSScC) and data from juvenile-onset adult SSc patients from the European Trials and Research Group (EUSTAR) cohort. We compared the clinical characteristics of the patients by descriptive statistics.ResultsWe extracted data of 187 jSSc patients from the jSScC and 236 patients from EUSTAR. The mean age at time of assessment was 13.4 years old in the jSScC and 32.4 years old in EUSTAR. The mean disease duration since first non-Raynaud was 3.0 years in jSScC and 18.5 years in the EUSTAR (Table 1).We found significant differences between the cohorts. There were more female patients in EUSTAR (87.7% versus 80.2%, p=0.04). More patients had diffuse subtype in jSScC (72.2% versus 40%, pTable 1.Clinical characteristics of juvenile onset SSc patients at time point of the inclusion into the juvenile scleroderma inception (jSScC) cohort and in the adult EUSTAR- cohortjSScCEUSTAR CohortP valueNumber of patients1872360.04Age in years, mean (SD)13.4 (3.6)32.4 (15.4)Female patients, n (%)150 (80.2%)207 (87.7%)jSSC Subtype, n (%)diffuse135 (72.2%)87 (38.1%)limited52 (27.8%)121 (53.3%)Age at Raynaud onset in years, mean (SD)10.0 (3.9)13.7 (9.1)Age at non-Raynaud onset in years, mean (SD)10.3 (3.9)11.7 (3.7)Duration since first Raynaud symptoms in years, mean (SD)3.4 (2.7)20.6 (15.9)Duration since first non-Raynaud symptoms in years, mean (SD)3.0 (2.7)18.5 (15.6)Raynaud´s, n (%)170 (90.9%)222 (94.9%)ANA positive, n (%)166 (91.7%)210 (92.9%)0.99Anti-Scl 70 positive, n (%)62 (34.4%)73 (33.3%)0.68Modified Rodnan Skin Score, mean (SD)5%Data missingModified Rodnan Skin Score, mean (SD)14.2 (11.7)12.1 (14.5)0.02Digital ulceration, n (%)At the time of inclusion33 (17.8)21 (26.6%)0.01In the past history100 (54.1%)34 (43%)Telangiectasia62 (37.4%)42 (53.2%)0.04FVC, mean (SD)84.1 (18.6)84 (22.4)0.96DLCO, mean (SD)75.4 (19.2)86.3 (19.9)Arterial hypertension, n (%)10 (5.4%)20 (8.5%)0.26Renal crisis, n (%)03 (1.3%)0.26Esophageal involvement, n (%)63 (33.7%)149 (63.7%)Intestinal involvement, n (%)62 (33.2%)56 (23.8%)0.04Articular involvement, n (%)34 (18.3%)27 (11.6%)0.06Muscular involvement, n (%)31 (19.3%)46 (19.8%)0.45ConclusionPatients with jSSc-onset who are currently adult age (defined as >18 years of age) are less frequently male and from the diffuse subset, have lower mRSS, less digital ulcers and intestinal involvement. This might represent a combination of both survival bias and/or be explained by the longer observation time with less active disease (i.e. natural progression decreased mRSS over time). Further long-term observational studies with jSSc patients are required to address this issue.Disclosure of InterestsNone declared

BackgroundCoronavirus 19 disease (COVID-19) represents the most important pandemic of the last century. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has produced more than 170 million cases and more than 3 million deaths. Due to the easy spread of the infection and the possibility of serious clinical manifestations, the role of anti-COVID 19 vaccination is essential. Vaccines with different mechanisms of action have been developed: mRNA-based, such as Biontech-Pfizer and Moderna, and viral vectored, such as AstraZeneca and Janssen. Despite possible adverse events, benefits afforded by these vaccines significantly outweigh potential risks associated with their administration in the general population.ObjectivesThis study aimed to evaluate incidence and severity of adverse events (AEs), secondary to vaccination, in patients with Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and Spondyloarthritis (SpA), immune-mediated diseases treated with immunomodulating drugs, by administering a questionnaire.Methods294 patients (201 f and 93 m) were enrolled with a diagnosis of arthritis (RA 28%, PsA 43%, SpA 28%).ResultsOf the 294 enrolled patients, 107 underwent COVID vaccination, 73% with Biontech-Pfizer vaccine, 20% Astrazeneca and 6% Moderna. 50% of patients completed the entire vaccination cycle.46% of patients presented AEs after the first dose of vaccine (45% of vaccinated with Biontech-Pfizer; 48% of vaccinated with Astrazeneca, 33% of vaccinated with Moderna). The most frequently observed AEs are: pain at the injection site (17%), fever (13%), headache (12%), myalgia (12%), fatigue (7.5%). Only 2.9% of patients had arthritis flares. The greatest trend of AEs was observed in patients with PsA (48%), and RA (26%).32% of patients receiving the second dose of vaccine presented AEs (40% Moderna, 32% Biontech-Pfizer). The most frequently observed AEs after the second dose are: pain at the injection site (4.7%), fever (9%), headache (2.8%), myalgia (6%). No patient had arthritis flare after the second dose. The greatest trend of AEs was observed in patients with SpA (66%).Only 11% of patients presented AEs after the administration of both doses.Thirteen percent of patients did not follow the clinician’s recommendations for immunomodulatory drug management, provided as per ACR or SIR recommendations.ConclusionThe incidence of adverse events in arthritis patients was in line with that of the general population, without presenting serious manifestations, such as thrombosis, and without indicating a preference on the type of vaccine.References[1]Tsai SC, Lu CC, Bau DT, Chiu YJ, Yen YT, Hsu YM, Fu CW, Kuo SC, Lo YS, Chiu HY, Juan YN, Tsai FJ, Yang JS. Approaches towards fighting the COVID‑19 pandemic (Review). Int J Mol Med. 2021 Jan;47(1):3-22. doi: 10.3892/ijmm.2020.4794. Epub 2020 Nov 20. PMID: 33236131; PMCID: PMC7723515.[2]Hodgson SH, Mansatta K, Mallett G, Harris V, Emary KRW, Pollard AJ. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect Dis. 2021 Feb;21(2):e26-e35. doi: 10.1016/S1473-3099(20)30773-8. Epub 2020 Oct 27. PMID: 33125914; PMCID: PMC7837315.Disclosure of InterestsNone declared

BackgroundThe Janus kinase (Jak) - signal transducer and activator of transcription (STAT) pathway has 4 Jak proteins and 7 STAT factors that mediate intracellular downstream of cytokine receptors. Targeted small-molecule therapies with different bond affinity to Jak proteins have been demonstrated effective in rheumatoid arthritis (RA) treatment, but the clinical significance of selective inhibition remains unclear.ObjectivesTo explore the effect of selective inhibition of Jak-STAT pathway in peripheral blood mononuclear cells (PBMC) from RA patients compared to healthy donors (HD).MethodsIn vitro Jak inhibition of the subunit 3 of phosphorylated (p) than activated STAT was measured by flow cytometry in peripheral blood mononuclear cells (PBMC) from RA patients with active disease (DAS28>5.1) naïve to any DMARDs (n.5) and HD (n.5), following recombinant human 0.1 ng/ml IL-6 (Peprotech – NJ, USA) stimulation. After blood separation, PBMC were overnight incubated with IC50 concentrations of selective Jak1-, Jak2-, Jak3- and Tyk2-inhibitors (Biovision Inc. – CA, USA) with or without IL-6 stimulation. Mean fold-increase of pSTAT3 was then compared in presence of different compounds stimulation.ResultsMean pSTAT3 activity after overnight incubation was significantly higher in RA patients compared to HD (37%; 95CI 8.2-56.7 vs 17.9%; 95CI 4.6-21 – p=0.01). After IL-6 stimulation, a 2-fold and a 1.4-fold increase in pSTAT3 levels was observed in PBMC from RA patients and HD, respectively. In unstimulated PBMC from HD Jak-inhibitors didn’t significantly reduced pSTAT3 activity. In CD14+ cells from RA patients, pSTAT3 activity was reduced with no differences between all four selective Jak-inhibitors, while in CD4+ cells only Jak1-inhibition was able to reduce by 40% pSTAT3 activity. After IL-6 stimulation, the co-culture with Jak1- or JaK3- selective inhibitors was able to significantly reduce pSTAT3 levels in CD4+ lymphocytes, by an average of 20%. While in CD14+ monocytes Jak1-, Jak2- and Jak3- selective inhibitors were able to reduce pSTAT3 activity by a mean of 30%. Tyk-2 selective inhibitor did not interfere with STAT3 activation by IL-6 stimulation of PBMC from RA patients and HD.ConclusionJak/STAT3 activity of PBMC from RA patients with active disease may be differently modulated by specific inhibitors. Selectivity of Jak-inhibitors seems more relevant in lymphocytes after IL-6 stimulation. These preliminary findings may explain discrepancies in effectiveness of selective Jak-inhibitors and pave the way for different choices in clinical practice.References[1]Tanaka Y, et al. Nat Rev Rheumatol. 2022 Jan 5:1–13.[2]Traves PG, et al. Ann Rheum Dis. 2021 Jul;80(7):865-875.[3]Choy EH. Rheumatology (Oxford). 2019 Jun 1;58(6):953-962.Disclosure of InterestsNone declared