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Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knock-in mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region- and time- specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2∷eGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.

Background:Systemic vasculitides are a group of inflammatory multisystem diseases with recurrent relapses and chronic damage due to disease and its treatments. The extent to which having this condition impacts the psychological health of patients is yet to be fully understood.Objectives:To quantify the psychological impact of living with systemic vasculitides.Methods:We cross-sectionally evaluated a cohort of patients with systemic vasculitides seen at diagnosis or follow-up in our center, between April 1st and December 31st, 2023. Data collected from each patient included their demographic and clinical data, as well as their medical history.We administered the symptom checklist revised (SCL-90-R) to measure distress related to 9 psychological dimensions, i.e. somatization (SOM), obsessive compulsion (OC), interpersonal sensitivity (IS), depression (DEP), anxiety (ANX), hostility (HOS), phobic anxiety (PHOB), paranoid ideation (PAR), psychoticism (PSY), and providing 3 global indices of distress, i.e. global severity index (GSI, the average symptom intensity), positive symptom distress index (PSDI, average level of distress for those items that were endorsed), and positive symptom total (PST, i.e. total symptoms endorsed). Distress was categorized in 4 intensity levels (null, low, moderate and high) with respect to the Italian reference population. We applied loglinear model to investigate if different vasculitis vessel types correlated with different psychological distress.Results:By using the SCL-90-R checklist, we screened a total of 171 patients affected by systemic vasculitides (females 48.5%, mean age 65 years old, range: 21-88): 64% had small vessel vasculitis (SVV, of which 89% were ANCA-associated vasculitides), 29% had large vessel vasculitis (LVV, of which 79% were giant cell arteritis), 7% had variable vessel vasculitis (VVV, Behcet’s disease).Eight % of patients reported moderate-to-high intensity for PAR and HOS, while more than 20% for DEP and ANX. Thirty % of patients reported moderate-to-high intensity for SOM, which may be expected considering the confounding effect of being affected by systemic vasculitides. Less than 5% reported no symptoms in any dimensions, while 45% reported at least one dimension with moderate-to-high intensity, and 13% more than 4 dimensions (as shown in Figure 1A, representing percentage of outpatient with psychological distress and its intensity for each of the 9 dimensions and 3 global indexes).Active disease (as assessed by Birmingham vasculitis activity score >0) was associated with DEP, ANX, PSY, and PST (p<0.05); prednisone ≥5 mg/day was associated with ANX (p<0.05), while no dimensions were associated with different categories of immunosuppressive therapies. Notably, severe damage (Vasculitis Damage Index ≥5) associated with SOM, OC, DEP, ANX, GSI, and PSDI (p<0.05).Loglinear models showed associations of different vasculitis vessel types only with DEP (p=0.01) and SOM (p=0.03), as shown in the radar plots (Figure 1B).Figue 1.Conclusion:Patients affected by systemic vasculitides showed psychological distress in various symptomatic dimensions with respect to the Italian reference population, showing significant association with disease activity, glucocorticoid use, vasculitis vessel types, and particularly with severe damage. Our findings showed the need for psychological screening to identify distress due to vasculitis, aiming to reduce it with psychological interventions.REFERENCES:[1] Derogatis, L.R. and Unger, R. Symptom Checklist-90-Revised (2010).Acknowledgements:NIL.Disclosure of Interests:None declared.

Capturing agricultural heterogeneity through the analysis of farm typologies is key with regard to the design of sustainable policies and to the adoptability of new technologies. An optimal balance needs to be found between, on the one hand, the requirement to consider local stakeholder and expert knowledge for typology identification, and on the other hand, the need to identify typologies that transcend the local boundaries of single studies and can be used for comparisons. In this paper, we propose a method that supports expert-driven identification of farm typologies, while at the same time keeping the characteristics of objectivity and reproducibility of statistical tools. The method uses a range of multivariate analysis techniques and it is based on a protocol that favours the use of stakeholder and expert knowledge in the process of typology identification by means of visualization of farm groups and relevant statistics. Results of two studies in Zimbabwe and Kenya are shown. Findings obtained with the method proposed are contrasted with those obtained through a parametric method based on latent class analysis. The method is compared to alternative approaches with regard to stakeholder-orientation and statistical reliability.

To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related beta-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA(1c) (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference -1.0 +/- 0.2%; P < 0.001; baseline of all subjects combined 7.7 +/- 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference -0.9 +/- 0.3 mmol/l, P = 0.016; baseline 9.8 +/- 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 +/- 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 +/- 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 +/- 4 ml x min(-1) x m(-2), P = 0.036; baseline 246 +/- 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 +/- 1.0, P = 0.040; baseline 9.1 +/- 0.5). The change in adaptation index correlated to the change in A1C (r = -0.39, P = 0.004). This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves beta-cell function along with improved postmeal insulin sensitivity.

BackgroundDuring pregnancy, exchanges between mother and fetus are provided by the placenta. Defects in the early stages of placentation prevent the creation of a high-flow, low-resistance circle resulting in an impaired maternal-fetal exchange. The development of aberrant microcirculation leads to placental abnormalities, detectable by placental histologic examination [1].ObjectivesTo assess whether nailfold videocapillaroscopy (NVC), in combination with umbilical artery doppler ultrasound (UA-dU), can detect microvascular status during pregnancy [2]; and to evaluate if NVC follow-up during pregnancy might operate as a red flag biomarker of placental microcirculation abnormalities.MethodsWe conducted a longitudinal observational exploratory study on 54 healthy pregnant women (age range 26-46 y) within the 16th gestational week, excluding those with cardiovascular comorbidities. We performed clinical, UA-dU and NVC evaluation with an optical probe (200x magnification) at each trimester of pregnancy and post-partum [3]. We performed an after-birth placenta histology (abPH) in a subgroup of 20 women (among the 54 women) who developed complications during pregnancy (e.g., gestational hypertension) evaluated through optical microscopic technique, according to Amsterdam criteria [4].ResultsWe noticed over time, in the whole cohort, a statistically significant increase in neo-angiogenesis (p<0.05), considering the absolute count of microvessel ramifications (abnormal shapes) (Figure 1a). Conversely, we did not observe any statistically significant variation in capillary density (n/linear mm), microhaemorrhages or dilated capillaries over time. Besides, a statistically significant difference in the absolute number of capillaries in the first trimester between subjects with and without areas of placental dysmaturity (aberrant placental microcirculation) was detected at abPH (7.0/mm ± 0.82 vs 8.2/mm ± 0.62; p=0.030), (Figure 1b). A receiver operating characteristic curve was drawn for calculating the Area Under the Curve (AUC: 0.87; 95%CI: 0.66–1.00), identifying the optimal discriminatory cut-off value for prediction of placental dysmaturity areas (≤7.50/mm capillaries, sensitivity: 88.9%; specificity: 75.0%). Of note, a similar difference was confirmed at the third trimester, although not reaching statistical significance (p=0.06). Not any significant association was found between UA-dU and any of the assessed NVC parameters.ConclusionThis study confirms, in a large cohort of pregnant women, the NVC detection of increased neoangiogenesis over time, even during post-partum. In addition, this is the first report suggesting the possible role of NVC (capillary density) for the early detection of aberrant placental microcirculation noticeable at abPH. A study in pregnant patients affected by autoimmune connective tissue diseases has already started, using those findings as reference parameters.References[1]Rana S. et al. Circ Res, vol. 124, n. 7, pp. 1094–1112, Mar 2019.[2]Pacini G. et al. Microvasc Res, vol. 141, May 2022.[3]Smith V. et al. Autoimmun Rev vol. 19, n. 3. Elsevier B.V., Mar. 01, 2020.[4]Khong T.Y. et al. Arch Pathol Lab Med, Jul. 2016, vol. 140, n. 7, pp. 698–713Figure 1.a. Neo-angiogenesis (arrows) at the 3rd trimester (magnification 200x). b. Difference in the absolute number of capillaries in the 1st trimester between women with and without areas of placental dysmaturity at abPH.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Microvascular damage is a frequent feature in connective tissue diseases (CTDs) and can be easily detected trough nailfold videocapillaroscopy (NVC) (1,2). Mixed and Undifferentiated connective tissue diseases (MCTD and UCTD) do not show a specific and unique NVC pattern (3). However, a variety of microvascular abnormalities can occur in these two CTDs, both non-specific or specific for the scleroderma like-pattern (3-5). To retrospectively assess and compare nailfold microangiopathy observed by NVC in MCTD and stable UCTD versus primary Raynaud's phenomenon (PRP) (6). In addition, the aim was to correlate NVC findings with serum levels of autoantibodies (Abs) against extractable nuclear antigen (ENA) detected in UCTD. Files of fourty-six MCTD patients (Kasukawa's criteria) (mean age 42.8±16 SD years), fourty-seven UCTD patients (mean age 47.7±16.1 SD years), fifty-one PRP (mean age 45.9±17.3 SD years) were retrospectively evaluated in the study. Among UCTD and MCTD patients 95% of both showed Raynaud's phenomenon. Main NVC parameters (i.e. dilated capillaries, giant capillaries, microhemorrhages, abnormal shapes and number of capillaries) and related semiquantitative scale (score 0–3 for every parameter), were analyzed and compared between the two distinct CTD groups and PRP. Furthermore, ENA Abs (in particular, Ro/SSA, La/SSB, Scl70 and Jo1) were evaluated. The CTD patients were receiving different immunosuppressive treatments. Statistical analysis was performed by non-parametric tests. Among UCTD group, 36% of patients showed a normal NVC pattern, 53% had non-specific NVC abnormalities and 11% had a scleroderma like-pattern. The latter was significantly more frequent in MCTD than in UCTD (p<0.001), in fact 22 out of 46 (48%) MCTD patients presented a scleroderma-like pattern. On the other hand, normal pattern or non-specific NVC abnormalities were respectively found in 9% and 43% MCTD patients. Therefore, CTD patients showing giant capillaries, abnormal shapes (i.e. angiogenesis) and lower capillary density were significantly more affected by MCTD than UCTD (p<0.001). Finally, the absolute number of capillaries was found significantly lower in MCTD versus UCTD patients (mean 7±1.7 SD vs mean 9.2±1 SD, respectively, p<0.001). Not any statistical correlation was observed between NVC parameters and specific Abs ENA in UCTD. PRP showed a normal NVC pattern in 2% and non-specific capillary abnormalities in 98%, (including dilated capillaries and microhemorrhages). NVC features in UCTD patients seem very close to the pattern observed in PRP (mostly non-specific capillary abnormalities), conversely in MCTD the scleroderma-like pattern was found significantly prevalent together with a significant capillary number reduction. The transition from the scleroderma-like to the scleroderma pattern (mean systemic sclerosis) is matter of actual investigation. [1]Cutolo M. et al. Best Pract Res Clin Rheumatol 2008; 22:1093-108. [2]Sulli A, Ann Rheum Dis. 2008;67:885-7. [3]Smith V. et al. Autoimmunity Reviews 2020; 19:102458. [4]De Holanda Mafaldo DA, et al. Lupus. 2007; 16:254–8. [5]Smith V, et al. Ann Rheum Dis 2010; 69: 1092-96. [6]Antunes M, et al. RMD Open. 2019, 26;4. None declared

The development of new therapies for the treatment of type 2 diabetes requires robust, reproducible and well validated in vivo experimental systems. Mice provide the most ideal animal model for studies of potential therapies. Unlike larger animals, mice have a short gestational period, are genetically similar, often give birth to many offspring at once and can be housed as multiple groups in a single cage. The mouse model has been extensively metabolically characterized using different tests. This report summarizes how these tests can be executed and how arising data are analyzed to confidently determine changes in insulin resistance and insulin secretion with high reproducibility. The main tests for metabolic assessment in the mouse reviewed here are the glucose clamp, the intravenous and the oral glucose tolerance tests. For all these experiments, including some commonly adopted variants, we describe: (i) their performance; (ii) their advantages and limitations; (iii) the empirical formulas and mathematical models implemented for the analysis of the data arising from the experimental procedures to obtain reliable measurements of peripheral insulin sensitivity and beta cell function. Finally, a list of previous applications of these methods and analytical techniques is provided to better comprehend their use and the evidences that these studies yielded.

Background:VEXAS syndrome is an adult-onset, X-linked, life-threatening, autoinflammatory disease with predominant hematological involvement caused by somatic mutation in UBA1 gene whose pathophysiology is still unknown.Objectives:To achieve a molecular and phenotypic characterization of hematopoiesis of VEXAS patients and to develop cellular and humanized mouse models by gene editing.Methods:Six VEXAS patients (p.Met41>Thr; p.Met41>Val; p.Met41>Leu; c.118-1 G>C) were recruited from our Unit. Variant allele frequency (VAF) of UBA1 mutant cells was quantified by targeted sequencing in isolated hematopoietic lineages and hematopoietic stem/progenitor cells (HSPCs). Multiparametric immunophenotypic analysis and single cell RNA seq were performed on peripheral blood and bone marrow (BM), focusing on HSPCs. Circulating monocytes were analyzed by whole RNA-seq and metabolome analysis. Healthy age and sex-matched controls were included. To introduce UBA1 mutations and develop VEXAS models, cutting-edge gene editing technologies were adopted in healthy human HSPCs.Results:Targeted sequencing in VEXAS patients showed >0.8 VAF in HSPCs. Conversely, VAF largely differed across mature cells, averaging 0.81 in neutrophils, 0.64 in monocytes, 0.42 in NK, 0.07 in T cells, and 0.09 in B cells, supporting a myeloid skewing of mutant HSPCs. Multiparametric immunophenotypic analyses showed unbalanced composition of HSPCs in the BM, with 2-to-3-fold reduction of primitive stem cells, multipotent and lymphoid progenitors, and 2-fold increase of myeloid progenitors, compared to matched healthy individuals. HSPCs, myeloid-biased HSPCs and immature myeloid cells were increased by 3-to-4 fold in the circulation (p<0.03). Gene expression analysis of circulating monocytes displayed upregulation of inflammatory pathways and metabolic rewiring (Figure. 1, panels A-B). Metabolomic analyses confirmed hyperactivation of the glycolytic pathway and specific lipid metabolism (Figure. 1, C-D). Single-cell RNA-seq of bone marrow mononuclear cells identified a subpopulation of CD34+ cell specific of VEXAS patients and revealed upregulated stress response and immune activation pathways across VEXAS cell clusters compared with healthy controls. Models of VEXAS generated by gene editing recapitulated patients’ hematopoiesis and pathophysiology in vitro and in vivo. UBA1 mutations were installed at VAF>0.9 in HSPCs and generated a myeloid bias in vitro. Transplantation of edited HSPCs in immunodeficient mice resulted in a 100-fold reduction in circulating B cells, while NK and myeloid compartments were preserved. Human BM HSPCs were 5-fold lower than control mice, largely myeloid-biased and presented abnormal vacuolar morphology. Concordantly, VAF was >0.8 in myeloid cells and HSPCs and <0.3 in B cells. Figure 1. Panel A. Gene expression analysis of peripheral monocytes in VEXAS patients compared to controls. Panel B. Gene-enrichmed pathway analysis in VEXAS patients compared to controls. Panel C. Metabolic analysis in VEXAS patients compared to controls. Panel D. Metabolic-enriched pathway analysis in VEXAS patients compared to controls.Figure 1.Conclusion:Mutations in UBA1 drive expansion of HSPCs and enhance myelopoiesis-guided accumulation of myeloid precursors. Mutant lymphoid cells are negatively selected and their myeloid counterpart in peripheral blood displays upregulation of transcriptomic signatures and metabolic pathways indicative of inflammatory activation. Gene editing-based models hold promise to enable preclinical testing and validation of novel therapeutics to treat VEXAS syndrome.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Corrado Campochiaro: None declared, Raffaella Molteni: None declared, Guido Pacini: None declared, Martina Fiumara: None declared, Alessandro Tomelleri: None declared, Elisa Diral: None declared, Davide Stefanoni: None declared, Angelica Varesi: None declared, Alessandra Weber: None declared, Roberta Alfieri: None declared, Luisa Albano: None declared, Maddalena Panigada: None declared, Eleonora Cantoni: None declared, Daniele Canarutto: None declared, Luca Bassoricci: None declared, Pamela Quaranta: None declared, Angelo D’Alessandro: None declared, Marco Matucci-Cerinic: None declared, Raffaella Di Micco: None declared, Alessandro Aiuti: None declared, Fabio Ciceri: None declared, Ivan Merelli: None declared, Lorenzo Dagna: None declared, Serena Scala: None declared, Simone Cenci: None declared, Luigi Naldini: None declared, Samuele Ferrari: None declared, Giulio Cavalli Novartis, Novartis.

Aims/hypothesis B-type natriuretic peptide (BNP) is a hormone released from cardiomyocytes in response to cell stretching and elevated in heart failure. Recent observations indicate a distinct connection between chronic heart failure and diabetes mellitus. This study investigated the role of BNP on glucose metabolism. Methods Ten healthy volunteers (25 ± 1 years; BMI 23 ± 1 kg/m 2 ; fasting glucose 4.6 ± 0.1 mmol/l) were recruited to a participant-blinded investigator-open placebo-controlled cross-over study, performed at a university medical centre. They were randomly assigned (sequentially numbered opaque sealed envelopes) to receive either placebo or 3 pmol kg −1  min −1 BNP-32 intravenously during 4 h on study day 1 or 2. One hour after beginning the BNP/placebo infusion, a 3 h intravenous glucose tolerance test (0.33 g/kg glucose + 0.03 U/kg insulin at 20 min) was performed. Plasma glucose, insulin and C-peptide were frequently measured. Results Ten volunteers per group were analysed. BNP increased the initial glucose distribution volume (13 ± 1% body weight vs 11 ± 1%, p  < 0.002), leading to an overall reduction in glucose concentration ( p  < 0.001), particularly during the initial 20 min of the test ( p  = 0.001), accompanied by a reduction in the initial C-peptide levels (1.42 ± 0.13 vs 1.62 ± 0.10 nmol/l, p  = 0.015). BNP had no impact on beta cell function, insulin clearance or insulin sensitivity and induced no adverse effects. Conclusions/interpretation Intravenous administration of BNP increases glucose initial distribution volume and lowers plasma glucose concentrations following a glucose load, without affecting beta cell function or insulin sensitivity. These data support the theory that BNP has no diabetogenic properties, but improves metabolic status in men, and suggest new questions regarding BNP-induced differences in glucose availability and signalling in various organs/tissues. Trial registration: ClinicalTrials.gov: NCT01324739 Funding: The study was funded by Jubilée Fonds of the Austrian National Bank (OeNB-Fonds).

Fibroblast-to-myofibroblast transition is one of the fundamental steps involved in the fibrotic process that characterise systemic sclerosis (SSc) [1]. Myofibroblasts are α-smooth muscle actin (αSMA) positive cells that contribute to fibrosis through the excessive synthesis and deposition of extracellular matrix (ECM) proteins, primarily fibronectin (FN) and type I collagen (COL1) [2]. Among the cells involved in the fibrotic process of SSc, circulating fibrocytes seem to have an emerging role as an important source of fibroblasts and myofibroblasts [3]. Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis that interferes with the signalling pathways involved in the pathogenesis of fibrosis (4). Nintedanib was recently demonstrated to have a beneficial effect in patients with interstitial lung disease (ILD) associated with SSc (5). To investigate nintedanib effect in inhibiting the in vitro transition of circulating SSc fibrocytes into myofibroblasts and their pro-fibrotic activity. Circulating fibrocytes were obtained from 14 SSc patients (mean age 64±14 years), who fulfilled the 2013 ACR/EULAR criteria for SSc and that underwent complete disease staging in a day-hospital setting at the Rheumatology Division of Genoa University. Five age-matched healthy subjects (HSs) were also analysed. All SSc patients and HSs signed the informed consent and the local EC approved the study. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and plated on FN-coated dishes. After overnight culture, non-adherent cells were removed, and adherent cells were maintained in growth medium for 8 days (T8) to obtain fibrocytes [6]. T8-cultured SSc fibrocytes were maintained in growth medium (untreated cells) or treated with nintedanib 0.1μM and 1μM for 3 and 24 hours. Fibroblast specific protein-1 (S100A4) and αSMA, as markers of fibroblast/myofibroblast phenotype, together with COL1 and FN, were investigated by qRT-PCR and Western blotting. Non-parametric Mann-Whitney and Wilcoxon tests were used for the statistical analysis. Significantly elevated gene and protein expressions of αSMA, S100A4, COL1 and FN were observed in SSc fibrocytes compared to HS fibrocytes (gene: αSMA p<0.001; others p<0.0001; protein: all p<0.05). In accordance with the antibody positivity for Scl70 and the presence or absence of ILD at CT scan, SSc patients were grouped as either Scl70 positive patients with ILD (Scl70+ILD+) or Scl70 negative patients without ILD (Scl70-ILD-). Significant αSMA, S100A4, COL1 and FN gene expressions were found in fibrocytes from Scl70+ILD+ compared to HS fibrocytes (αSMA p<0.001; others p<0.0001). Moreover, fibrocytes from Scl70+ILD+patients showed a more significant gene expression of fibroblasts/myofibroblasts markers compared to Scl70-ILD-patients (p<0.01 for S100A4), whereas no differences were observed for ECM gene expression. Nintedanib reduced the gene and protein expression of αSMA, COL1 and FN in SSc fibrocytes compared to untreated ones with different statistical significance. Noteworthy, nintedanib significantly downregulated αSMA, S100A4, COL1 and FN gene expression (all p<0.05) in Scl70+ILD+fibrocytes, whereas only that of S100A4 and FN was significantly downregulated (p<0.05) in Scl70-ILD- fibrocytes compared to untreated cells. Nintedanib seems to downregulate in vitro the transition of fibrocytes into myofibroblasts and their pro-fibrotic activity, particularly in cells isolated from Scl70+ILD+SSc patients. [1]Cutolo M et al. Exp Rev Clin Immunol. 2019;15:753-64. [2]Van Caam A et al. Front. Immunol. 2018;9:2452.doi:10.3389/fimmu.2018.02452. [3]Distler JH et al. Arthritis Rheumatol. 2017;69:257-67. [4]Distler O et al. New Eng J Med. 2019; 380:2518-28. [5]Maher TB et al. Arthritis Rheumatol.2020.doi:10.1002/art.41576. [6]Cutolo M et al. Arthritis Res Ther. 2018;20:157.doi:10.1186/s13075-018-1652-6. We thank Stefano-Lutz Willing for the scientific support through the study. Stefano Soldano: None declared, Paola Montagna: None declared, Emanuele Gotelli: None declared, Samuele Tardito: None declared, Sabrina Paolino: None declared, Claudio Corallo: None declared, Carmen Pizzorni: None declared, Alberto Sulli: None declared, Carlotta Schenone: None declared, Greta Pacini: None declared, Vanessa Smith: None declared, Maurizio Cutolo Grant/research support from: I received grant/research support from Bristol-Myers Squibb, Boehringer, Celgene