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Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions that favour glucose metabolism. Its role in the heart is unknown. Here we show that Fgf21 −/− mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development. In addition, Fgf21 −/− mice exhibit enhanced induction of cardiac hypertrophy markers and pro-inflammatory pathways and show greater repression of fatty acid oxidation. Most of these alterations are already present in Fgf21 −/− neonates, and treatment with fibroblast growth factor 21 reverses them in vivo and in cultured cardiomyocytes. Moreover, fibroblast growth factor 21 is expressed in the heart and is released by cardiomyocytes. Fibroblast growth factor 21 released by cardiomyocytes protects cardiac cells against hypertrophic insults. Therefore, the heart appears to be a target of systemic, and possibly locally generated, fibroblast growth factor 21, which exerts a protective action against cardiac hypertrophy. Fibroblast growth factor 21 (FGF21) regulates energy metabolism in peripheral tissues. Here Planavila and colleagues show that FGF21 also acts directly on cardiomyocytes, thereby protecting mice against cardiac hypertrophy.

CD38 is a type II glycoprotein highly expressed on plasmablasts and on short- and long-lived plasma cells, but weakly expressed by lymphoid, myeloid, and non-hematopoietic cells. CD38 is a target for therapies aimed at depleting antibody-producing plasma cells. Systemic sclerosis (SSc) is an immune-mediated disease with a well-documented pathogenic role of B cells. We therefore analyzed CD38 expression in different subsets of peripheral blood mononuclear cells (PBMCs) from a cohort of SSc patients. Cell surface expression of CD38 was evaluated on PBMCs from SSc patients using eight-color flow cytometry analysis performed with a FacsCanto II (BD). Healthy individuals were used as controls (HC). Forty-six SSc patients (mean age 56, range 23-79 years; 38 females and 8 males), and thirty-two age- and sex-matched HC were studied. Twenty-eight patients had the limited cutaneous form and eighteen the diffuse cutaneous form of SSc. The mean disease duration was 7 years. Fourteen patients were on immunosuppressive therapy (14 MMF, 5 RTX). The total percentages of T, B and NK cells were not different between SSc and HC. Compared to HC, SSc patients had higher levels of CD3+CD38+ T cells (p<0.05), higher percentage (p<0.001) of CD3+CD4+CD25+FOXP3+ regulatory T cells, lower percentage (p<0.05) of CD3+CD56+ NK T cells. Moreover, SSc patients had higher levels of CD24 CD19+CD38 regulatory B cells than HC (p<0.01), while the amount of CD24+CD19+CD38+CD27+ memory B cells was lower (p<0.001). Finally, the percentages of circulating CD38 CD27+ plasmablasts and CD138+CD38 plasma cells were both higher in the SSc group than in HC (p<0.001). We did not observe any correlations between these immunophenotypes and disease subsets or duration, and ongoing immunosuppressive treatment. The increased expression of CD38 in peripheral blood plasmablasts and plasma cells of SSc patients may suggest this ectoenzyme as a candidate therapeutic target, under the hypothesis that depletion of these cells may beneficially downregulate the chronic immune response in SSc patients. Validation of this data in multicenter cohorts shall be obtained prior to clinical trials with existing anti-CD38 drugs.

Nowadays Nuclear Magnetic Resonance diffusion (dNMR) measurements of water molecules in heterogeneous systems have broad applications in material science, biophysics and medicine. Up to now, microstructural rearrangement in media has been experimentally investigated by studying the diffusion coefficient ( D ( t )) behavior in the tortuosity limit. However, this method is not able to describe structural disorder and transitions in complex systems. Here we show that, according to the continuous time random walk framework, the dNMR measurable parameter α, quantifying the anomalous regime of D ( t ), provides a quantitative characterization of structural disorder and structural transition in heterogeneous systems. To demonstrate this, we compare α measurements obtained in random packed monodisperse micro-spheres with Molecular Dynamics simulations of disordered porous media and 3D Monte Carlo simulation of particles diffusion in these kind of systems. Experimental results agree well with simulations that correlate the most used parameters and functions characterizing the disorder in porous media.

Background:Systemic sclerosis (SSc) is a multiorgan disease but, to date, only few definitions of the various organ manifestation specific for SSc exist. When available, these definitions are mainly derived from other diseases, i.e. interstitial lung disease (ILD), where definitions are adopted from idiopathic pulmonary fibrosis (IPF). For comparison of clinical studies and inclusion of patients in randomized clinical trials, standardization of definitions for organ involvement and behaviour over time is of utmost importance.Objectives:To establish expert consensus on definitions of presence of organ involvement, severity of involvement, progression, stability and improvement of organ involvement, and end-stage organ disease.Methods:Ten SSc experts from EUSTAR centres formed the steering committee to conduct the EUSTAR study CP-125. In the first stage, a list of items for the definitions on different organs was created based on a narrative literature search and based on availability of the variables collected in the EUSTAR database. In the second step, using an online survey, the experts were asked to assess the proposed items and add additional items felt to be important to define the respective definitions. Finally, during four online meetings, the steering committee discussed the previous results using the nominal group technique (NGT) and voted on each of the statements (Figure 1). The parameters voted for by more than 75% of the experts were regarded as acceptable to be included in the different definitions.Results:The literature search revealed 179 definitions from 820 papers. After expert evaluation, 199 items were suggested for 9 organ domains including (1) Lung - ILD; (2) Lung – pulmonary hypertension (PH); (3) Heart; (4) Kidney; (5) Skin; (6) Digital ulcers; (7) Arthritis; (8) Muscle; (9) Gastrointestinal tract. During the NGT meetings, definitions for five categories were discussed in each organ domain including the presence of organ involvement, severity of organ involvement, disease progression, disease improvement and end-stage organ involvement. The list of items selected by the online survey was presented and each voting member was asked to discuss the relevance of these items. Of 74 tools proposed and endorsed items to describe organ involvement in SSc; 9 definitions for presence, 7 definitions for severity, 9 definitions for progression, 4 definitions for improvement and 4 for end-organ disease were agreed on (Table 1).Conclusion:A core set of data driven, consensus-based definitions for different organ involvements and disease courses has been defined applying a robust and comprehensive methodology. These definitions are recommended by this SSc expert group to be used as interim tools for research studies.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Anna-Maria Hoffmann-Vold Boehringer Ingelheim, Boehringer Ingelheim, Janssen, Medscape, Merck Sharp & Dohme, Novartis and Roche. Consultant for ARXX, BMS, Boehringer Ingelheim, Genentech, Janssen, Medscape, Merck Sharp & Dohme and Roche., Boehringer Ingelheim, Janssen, Liubov Petelytska Research grant from Swiss National Research Foundation/Scholars at risk, Imon Barua: None declared, Cosimo Bruni Boehringer Ingelheim, Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis Foundation for Bio-medical Research, EMDO Foundation. Educational grants from AbbVie and Wellcome Trust. Congress participation support from Boehringer Ingelheim., Corrado Campochiaro: None declared, Ana Maria Gheorghiu: None declared, Alain LESCOAT: None declared, Madelon Vonk Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen Pharmaceutical Companies of Johnson & Johnson, MSD, Novartis, and Roche, Boehringer Ingelheim and Janssen Pharmaceutical Companies of Johnson & Johnson, Boehringer Ingelheim, Ferrer, Galapagos and Janssen Pharmaceutical Companies of Johnson & Johnson, Ilaria Galetti: None declared, Armando Gabrielli: None declared, Oliver Distler 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB, Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Co-founder of CITUS AG., 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB, Boehringer Ingelheim, Kymera, Mitsubishi Tanabe.

Schistosomiasis remains one of the most prevalent parasitic diseases in developing countries. After malaria, schistosomiasis is the most important tropical disease in terms of human morbidity with significant economic and public health consequences. Although schistosomiasis has recently attracted increased focus and funding for control, it has been estimated that less than 20% of the funding needed to control the disease in Africa is currently available. In this article the following issues are discussed: the rationale, development and objectives of the Schistosomiasis Control Initiative (SCI)-supported programmes; the management approaches followed to achieve implementation by each country; mapping, monitoring and evaluation activities with quantifiable impact of control programmes; monitoring for any potential drug resistance; and finally exit strategies within each country. The results have demonstrated that morbidity due to schistosomiasis has been reduced by the control programmes. While challenges remain, the case for the control of schistosomiasis has been strengthened by research by SCI teams and the principle that a national programme using ‘preventive chemotherapy’ can be successfully implemented in sub-Saharan Africa, whenever the resources are available. SCI and partners are now actively striving to raise further funds to expand the coverage of integrated control of neglected tropical diseases (NTDs) in sub-Saharan Africa.

Modern pixel detectors, particularly those designed and constructed for applications and experiments for high-energy physics, are commonly built implementing general readout architectures, not specifically optimized in terms of speed. High-energy physics experiments use bidimensional matrices of sensitive elements located on a silicon die. Sensors are read out via other integrated circuits bump bonded over the sensor dies. The speed of the readout electronics can significantly increase the overall performance of the system, and so here novel forms of readout architectures are studied and described. These circuits have been investigated in terms of speed and are particularly suited for large monolithic, low-pitch pixel detectors. The idea is to have a small simple structure that may be expanded to fit large matrices without affecting the layout complexity of the chip, while maintaining a reasonably high readout speed. The solutions might be applied to devices for applications not only in physics but also to general-purpose pixel detectors whenever online fast data sparsification is required. The paper presents also simulations on the efficiencies of the systems as proof of concept for the proposed ideas.

Background:In recent years, an improvement in the survival rate of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) has been recorded, at least partially attributed to the availability of novel treatment strategies[1]. Upfront combination therapy and treatment adapted to risk stratification of PAH have been recommended in SSc-PAH at time of diagnosis[2]. Recent work does, however, show that a substantial proportion of patients are still not treated according to the current treatment recommendations[3].Objectives:We aimed to characterize untreated SSc-PAH patients from the EUSTAR database and compare outcomes across the patient groups who did and did not receive upfront therapy.Methods:We assessed patients in the EUSTAR database who fulfilled the criteria for SSc-PAH according to the new hemodynamic definition of PAH (EUSTAR Project Number: CP122). We excluded patients already on PAH-specific treatment or who had severe interstitial lung disease (ILD), defined as an extent of ILD on HRCT >20% or a FVC <70% in the presence of ILD without available quantification. We defined two mutually SSc-PAH patient groups: (1) those who did not receive upfront treatment and (2) the upfront treatment group who received either mono- or combination therapy with endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), and/or prostanoids within 3 months from right heart catheterization. Higher and lower mPAP and PVR groups were defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary vascular resistance (PVR) >3 WU, and mPAP 21-24 mmHg or PVR 2-3 WU, respectively. Risk stratification was assessed by COMPERA 2.0. Transplant-free survival was evaluated using Kaplan-Meier analysis and log-rank test. The impact of no upfront treatment on mortality was assessed using Cox regression adjusted for age, sex, DLCO, hemodynamic- and risk groups, and pre-existing treatment with ERA, PDE5i, or intermittent prostanoids for Raynaud’s and digital ulcers (DUs).Results:Of the 890 patients who had right heart catheterization, 359 were eligible (Table 1). Over a median observation period of 3.4 (Q1-Q4: 1.4-6.1) years, 146 (41%) of the patients died and 11 (4%) were lung transplanted. The patient group with no upfront treatment had a lower risk profile at the time of SSc-PAH diagnosis, including a lower WHO functional class, a longer 6-min walk distance, and lower NT-proBNP levels (Table 1). Additionally, they had a higher DLCO and better hemodynamics, with more patients in the lower mPAP and PVR group (Table 1). A higher proportion of patients in the no upfront treatment group were on treatment for Raynaud’s and DUs, which may have had an impact on the decision to not start upfront treatment (Table 1). While comorbidities and SSc-specific organ manifestations likely influence PAH treatment decisions, we found no differences in the prevalence of diastolic dysfunction and limited ILD between the groups (Table 1). The proportion of upfront treatment increased with higher mPAP and PVR group, treatment-naïve status, and SSc-PAH diagnosis after 2015; the time when upfront combination therapy was first recommended (Figure 1A). Additionally, patients at higher risk by the COMPERA 2.0 tool did more often receive upfront treatment (Figure 1B). While unadjusted survival did not differ between the SSc-PAH patient group who received upfront treatment and the group who did not (Table 1), multivariable Cox regression analysis showed that no upfront treatment was significantly associated with increased mortality compared to upfront treatment, independent of hemodynamic group, risk stratification, and pre-existing therapies (Figures 1C and D).Conclusion:Despite a lower risk profile in SSc-PAH patients that were not treated upfront, our findings indicate that no upfront treatment is associated with worse survival. Hence, this study provides data that strengthens the recommendation of upfront treatment for SSc-PAH, regardless of hemodynamics, risk stratification, and pre-existing therapies.REFERENCES:[1] Khanna, D., et al., Arthritis Rheumatol, 2021.[2] Humbert, M., et al., Eur Heart J, 2022.[3] Distler, O., et al., Rheumatology, 2023.Acknowledgements:The authors thank all EUSTAR collaborators.Disclosure of Interests:Hilde Jenssen Bjørkekjær Janssen, Cosimo Bruni Eli-Lilly, Boehringer Ingelheim, Research grants from Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis Foundation for Bio-medical Research. Educational grants from AbbVie and Wellcome Trust. Congress participation support from Boehringer Ingelheim., Cathrine Brunborg: None declared, Patricia Carreira: None declared, Paolo Airò Bristol Myers Squibb, Bohringer Ingelheim, Novartis, Bristol Myers Squibb, Support for attending meetings and/or travel: CSL Behring, Janssen, Roche, Bristol Myers Squibb, Eli Lilly, Carmen P. Simeón-Aznar Janssen, MSD and Boehringer Ingelheim, Boehringer Ingelheim, Marie-Elise Truchetet Abbvie, Boehringer, Pfizer, MSD, Abbvie, Lilly, Alessandro Giollo Participation on a Data Safety Monitoring Board or Advisory Board: Boheringer, Alexandra Balbir-Gurman: None declared, Mickael Martin GlaxoSmithKline France, Boehringer Ingelheim, CSL Behring France, Christopher P Denton Janssen, GlaxoSmithKline, Boehringer Ingelheim, Janssen, GlaxoSmithKline, Bayer, Sanofi-Aventis, Boehringer Ingelheim, Roche, CSL Behring, Corbus, Acceleron, Horizon, Arxx Therapeutics, Lilly, Novartis, Certa, Abbvie, Arxx Therapeutics, Horizon, GlaxoSmithKline, Armando Gabrielli: None declared, Håvard Fretheim Boehringer ingelheim, Bayer, Helle Bitter Boehringer, Øyvind Midtvedt: None declared, Kaspar Broch Amgen, AstraZeneca, Boehringer, Novartis, Novo Nordisk, Pharmacosmos, Pfizer, Pfizer, Pharmacosmos, Boehringer, AstraZeneca, Arne Andreassen Janssen, Janssen, Sverre Høie: None declared, Yoshiya Tanaka Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Mitsubishi-Tanabe, Eisai, Chugai, Taisho, Gabriela Riemekasten: None declared, Ulf Müller-Ladner: None declared, Marco Matucci-Cerinic: None declared, Ivan Castellví: None declared, Elise Siegert: None declared, Eric Hachulla Johnson & Johnson, GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Bayer, GSK, Roche-Chugai, Sanofi-Genzyme, GSK, Roche-Chugai, Sanofi-Genzyme, Øyvind Molberg: None declared, Oliver Distler Boehringer Ingelheim, Janssen, Medscape, CITUS AG, 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB., Anna-Maria Hoffmann-Vold Boehringer Ingelheim, Boehringer Ingelheim, Janssen, Medscape, Merck Sharp & Dohme, Novartis and Roche, ARXX, BMS, Boehringer Ingelheim, Genentech, Janssen, Medscape, Merck Sharp & Dohme and Roche, Boehringer Ingelheim, Janssen.

Background:Previous studies reported a high prevalence of cognitive dysfunction in systemic sclerosis (SSc). Cognitive impairment was estimated to involve 60% to 80% of SSC patients and to be correlated with older age, disease severity, diffuse cutaneous subset and poor quality of life.Objectives:The aim of our study was to evaluate the association between cognitive impairment, nutritional status and the quality of life of SSc patients.Methods:Sixty-eight consecutive SSc patients followed at our Institution were evaluated for cognitive impairment using the validated Italian version of the Montreal Cognitive Assessment (MoCA). Scores <26 were considered abnormal. We also assessed other domains and quality of life measures such as UCLA SCTC GIT 2.0 for gastrointestinal involvement, BDI-II and PHQ-9 for anxiety and depression, EAT-10 for dysphagia symptoms, SHAQ and SF-36 for function and quality of life (QoL). The risk and the presence of overt malnutrition were assessed using the MUST questionnaire and the GLIM criteria, respectively. Clinical and demographic parameters such as age, sex, BMI, disease subset, organ involvement, autoantibody profile and modified Rodnan Skin Score were also recorded for each patient. Data were analysed by Student t-test or chi-square test and regression analyses were used to assess the association between variables.Results:A total of 68 SSc patients [47 (69.1%) limited SSc (lSSc) and 21 (30.9%) with diffuse SSc (dSSc), 59 female; mean age 60.2 (±13.4) years; mean disease duration 9 (±8.2) years; mean mRSS 8.1 (±7.6)] were included in the study.Cognitive impairment was identified in 30 (44.1%) SSc patients; the mean MoCA score was 24.7 (±4.3). According to GLIM criteria, 16 (23.5%) patients were malnourished. Compared to patients with a MoCA≥26, patients with cognitive impairment were older (p<0.001), had more comorbidities (p<0.0001) and a worse QoL as assessed by the physical and general health domains of the Sf-36 (p<0.05). Malnourished patients were significantly more dysphagic (p<0.01) and had a worse HAQ (p<0.01) compared to well-fed patients. On regression analyses, cognitive impairment was related to increasing age (OR 1.08, 95%CI 1.03 to 1.14, p=0.001), but not to malnutrition, disease subset or symptoms. Malnutrition was associated with dysphagia (OR 1.10, 95%CI 1.01 to 1.20, p=0.01) and HAQ score (OR 2.69, 95%CI 1.24 to 5.82, p=0.01), but was not predicted by cognitive impairment.Conclusion:Cognitive dysfunction is frequently observed in SSc patients and mostly associated with increasing age and number of comorbidities. Malnutrition and cognitive impairment are both associated to QoL but seem to be unrelated.Disclosure of Interests:None declared

Objectives:This study investigated the long-term effects of bosentan, an oral endothelin ETA/ETB receptor antagonist, in patients with pulmonary arterial hypertension (PAH) exclusively related to connective tissue diseases (CTD).Methods:A total of 53 patients with PAH related to connective tissue diseases (PAH–CTD) in World Health Organization (WHO) functional class III received bosentan 62.5 mg twice a day for 4 weeks and then 125 mg twice a day for 44 weeks in this open non-comparative study. Assessments at weeks 16 and 48 included WHO class, clinical worsening, quality of life (Short-Form Health Survey (SF-36) and health assessment questionnaire (HAQ) modified for scleroderma), and survival (week 48 only). Safety and tolerability were monitored throughout the study.Results:At week 48, WHO class improved in 27% of patients (95% CI 16–42%) and worsened in 16% (95% CI 7–29%). Kaplan–Meier estimates were 68% (95% CI 55–82%) for absence of clinical worsening and 92% (95% CI 85–100%) for survival. Overall changes in quality of life were minimal. There were no unexpected side effects observed during the study.Conclusions:In most patients, bosentan was associated with improvement or stability of clinical status. The 92% estimate for survival at 48 weeks is a significant achievement in this patient population.

BackgroundEULAR recommendations for treatment for Systemic Sclerosis (SSc) were last updated in 2017, based on literature up to the end of 2014. The treatment recommendations are among the most cited publication in the field, reflecting their utility both in clinical practice and academic research. In the past 8 years, several important advances have been achieved by the scientific community, with new treatments becoming available and accepted by regulatory authorities.ObjectivesTo update the 2017 EULAR recommendations for treatment of SSc, including answers to the 2017 research agenda, new therapeutic questions, and the wealth of newly available evidence.MethodsUpdate of previous recommendations was endorsed by EULAR and performed according to the validated methodology. The task force was composed according to recent EULAR guidelines for inclusivity of underrepresented areas of Europe and it consisted of 27 members, including a EULAR endorsed methodologist, 4 fellows, a librarian, one Allied Health Professional and two patient representatives, identified by the Federation of European Scleroderma Associations (FESCA). All centres from the EULAR Scleroderma Trials and Research group (EUSTAR) were invited to review previous questions for Systematic Literature Review (SLR) and propose new ones according to a standardised Delphi approach. A Nominal Group Technique (NGT) exercise was implemented in two rounds for the definition of questions with an 80% agreement threshold. The SLR was conducted with an end date of June 2022, and manually updated to December 2022. Particular attention was dedicated to the 2017 research agenda and new available evidence with matters for detailed discussion and new research agenda also agreed during the NGT.ResultsSixty-seven clinical questions addressing 24 different interventions were prioritised by the task force for the SLR. The results of the SLR were categorised by level of evidence and grade of recommendations and discussed during the NGT meeting. The procedure resulted in 21 recommendations (instead of 16 in 2017) in 8 clinical domains related to SSc symptoms and organ involvements, including Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease, gastrointestinal manifestations and arthritis. Most of the new recommendations were in the field of skin fibrosis and interstitial lung disease, consistent with the research agenda set in 2017. These included recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. None of these therapies were present in the 2017 recommendations. Important additions to the future research agenda included targeted therapies for the management of musculoskeletal and gastrointestinal manifestations, calcinosis and the local management of digital ulcers.ConclusionThe 2023 updates of EULAR recommendations include the first set of synthetic and biological targeted therapies recommended as disease modifying agents for key fibrotic manifestations of systemic sclerosis. While a disease modifying agent or strategy for a comprehensive approach appropriate for all SSc patients is still missing, numerous advances have been achieved since 2017. New, strong evidence is now available to clinicians to better manage patients with this life-threatening condition.Reference[1]Kowal-Bielecka O, Fransen J, Avouac J, et al. Ann Rheum Dis 2017;76:1327-1339Acknowledgements:NIL.Disclosure of InterestsFrancesco Del Galdo Speakers bureau: Astra-Zeneca, Janssen, Consultant of: Astra Zeneca, Boehringer-Ingelheim, Capella, Chemomab, Janssen, Mitsubishi-Tanabe, Grant/research support from: Abbvie, AstraZeneca, Boheringer-Ingelheim, Capella, Chemomab, Kymab, Janssen, Mitsubishi-Tanabe, Alain LESCOAT: None declared, Philip G Conaghan: None declared, Lidia P. Ananyeva Consultant of: Boehringer Ingelheim and Biocad, Alexandra Balbir-Gurman: None declared, Eugenia Bertoldo: None declared, Vladimira Boyadzhieva: None declared, Ivan Castellví Speakers bureau: Boehringer Ingelheim, Kern, Galápagos, Topandur, & Janssen- Cilag, Consultant of: Boehringer Ingelheim, Kern, Galápagos, Topandur, & Janssen- Cilag, Jelena Colic: None declared, Christopher P Denton Speakers bureau: GlaxoSmithKline, Galapagos, Boehringer.Ingelheim, Roche, CSL Behring, Corbus, Horizon,Capella Bioscience and Arxx Therapeuti, Consultant of: GlaxoSmithKline, Galapagos, Boehringer.Ingelheim, Roche, CSL Behring, Corbus, Horizon,Capella Bioscience and Arxx Therapeuti, Grant/research support from: GlaxoSmithKline, Galapagos, Boehringer.Ingelheim, Roche, CSL Behring, Corbus, Horizon,Capella Bioscience and Arxx Therapeuti, Oliver Distler Speakers bureau: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur, Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur, Khadija El Aoufy: None declared, Jenny Emmel: None declared, Sue Farrington: None declared, Armando Gabrielli: None declared, Ilaria Galetti: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Jannsen, Medscape, Merck Sharp & Dohme and Roche, Consultant of: ARXX, Boehringer Ingelheim, Genentech, Jannsen, Medscape, Merck Sharp & Dohme and Roche, Grant/research support from: Boehringer Ingelheim, Jannsen, Otylia Kowal-Bielecka Speakers bureau: Abbvie, Boehringer Ingelheim, CSL Behring, Janssen-Cilag, Medac, MSD, Novartis, Pfizer, Sandoz, Consultant of: Abbvie, Boehringer Ingelheim, CSL Behring, Janssen-Cilag, Medac, MSD, Novartis, Pfizer, Sandoz, Grant/research support from: Abbvie, Boehringer Ingelheim, CSL Behring, Janssen-Cilag, Medac, MSD, Novartis, Pfizer, Sandoz, Marco Matucci Cerinic Speakers bureau: Bayer,Biogen, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Inventiva,Lilly, MSD, Sandoz, Consultant of: Bayer,Biogen, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Inventiva,Lilly, MSD, Sandoz, Grant/research support from: Bayer,Biogen, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Inventiva,Lilly, MSD, Sandoz, Ulf Müller-Ladner Speakers bureau: BMS, Galapagos, Medac, Novartis, Janssen, Lilly, Boehringer, Consultant of: BMS, Galapagos, Medac, Novartis, Janssen, Lilly, Boehringer, Predrag Ostojic Speakers bureau: Abbvie, Eli Lilly, Boehringer Ingelheim, Novartis, MSD, Pfizer, Sandoz, Berlin Chemie Menarini, Amicus, EL Pharma, Consultant of: Abbvie, Eli Lilly, Boehringer Ingelheim, Novartis, MSD, Pfizer, Sandoz, Berlin Chemie Menarini, Amicus, EL Pharma, Simona Rednic Speakers bureau: Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Ewopharma,Janssen, Novartis, Pfizer, Sanofi, Sandoz, Consultant of: Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Ewopharma,Janssen, Novartis, Pfizer, Sanofi, Sandoz, Grant/research support from: Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Ewopharma,Janssen, Novartis, Pfizer, Sanofi, Sandoz, Tânia Santiago: None declared, Yossra A. Suliman: None declared, Anna Tarasova: None declared, Madelon Vonk Speakers bureau: Boehringer Ingelheim, Ferrer, Galapagos, GSK, Janssen, MSD and Novartis, Consultant of: Boehringer Ingelheim, Ferrer, Galapagos, GSK, Janssen, MSD and Novartis, Yannick Allanore Consultant of: AbbVie, AstraZeneca, Bayer, Boehringer-Ingelheim, Mylan, Janssen, Medsenic, Prometheus, Sanofi, Roche, Grant/research support from: Alpine Immunosciences, Medsenic, OSE Immunotherapeutics.