The clinical heterogeneity of adult onset Still's disease may underlie different pathogenic mechanisms. Implications for a personalised therapeutic management of these patients.

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown aetiology usually affecting young adults and manifesting with a clinical triad of spiking fever, arthritis, and evanescent cutaneous rash. AOSD may be considered a highly heterogeneous disease, despite a similar clinical presentation, the disease course may be completely different. Some patients may have a single episode of the disease whereas others may evolve toward a chronic course and experience life-threatening complications. On these bases, to dissect the clinical heterogeneity of this disease, four different subsets were identified combining the manifestations at the beginning with possible diverse outcomes over time. Each one of these derived subsets would be characterised by a prominent different clinical feature from others, thus proposing dissimilar underlying pathogenic mechanisms, at least partially. Consequently, a distinct management of AOSD may be suggested to appropriately tailor the therapeutic strategy to these patients, according to principles of the precision medicine. These findings would also provide the rationale to recognise a different genetic and molecular profile of patients with AOSD. Taking together these findings, the basis for a precision medicine approach may be suggested in AOSD, which would drive a tailored therapeutic approach in these patients. A better patient stratification may also help in arranging specific designed studies to improve the management of patients with AOSD. Behind these different clinical phenotypes, distinct endotypes of AOSD may be suggested, probably differing in pathogenesis, outcomes, and response to therapies.

Bosentan effect on echocardiographic systolic pulmonary arterial pressure in systemic sclerosis-related pulmonary hypertension: a systematic review and metanalysis.

OBJECTIVES: Bosentan is a dual endothelin receptor antagonist approved for the treatment of SSc digital ulcers (DU) and pulmonary arterial hypertension (PAH). Systolic pulmonary arterial pressure (sPAP) is a relevant parameter for the follow-up and prognosis of SSc-PAH. The therapeutic magnitude of bosentan in SSc-PAH is not fully understood, thus we aim to establish the degree of sPAP reduction in bosentan treated SSc-PAH patients. METHODS: We performed a systematic literature review in three databases from January 2000 to June 2023, involving sPAP measurement at transthoracic echocardiography of SSc patients before and after starting bosentan. Following the study quality assessment and data extraction, we performed random-effects meta-analysis and Egger's test for publication bias. Stratified analysis was performed for mono-/combination therapy, follow up duration (≤1 year), indication for bosentan therapy (PAH or DU/mixed). RESULTS: In the 11 selected manuscripts, sPAP mean difference before and after bosentan therapy was - 5.63mmHg (CI95% -9.79 to -1.48, p=0.0078). In stratified analysis, sPAP mean was significantly different before and after bosentan therapy only for studies considering < 1 year of follow-up (p=0.0020), monotherapy (p=0.0140) and the strict indication for PAH (p=0.0002). CONCLUSIONS: Bosentan significantly decreases sPAP, a relevant prognostic marker, especially in overt SSc-PAH. However, bosentan did not decrease sPAP when started for DU/mixed indication nor for follow-up>1 year. The burden of publication bias was significant. Therefore, further studies are required to assess bosentan's haemodynamic effect in high-risk patients for SSc-PAH.

Association between Patient Acceptable Symptom State and disease activity in psoriatic arthritis is disrupted by confounders, including comorbid fibromyalgia.

OBJECTIVES: Due to the prevalence of fibromyalgia in psoriatic arthritis (PsA) patients, any evaluation about PsA-specific patient-reported outcomes (PROs) should take in account the possible bias related to this comorbidity. Patient acceptable symptom state (PASS) is a patient-reported measure evaluating the acceptable and/or satisfactory level of symptoms in rheumatic diseases, which has been proposed as a disease activity index, in patients with PsA. Thus, this study was designed to analyse if the association between PASS and PsA disease activity may be biased by the presence of comorbid fibromyalgia. METHODS: A multi-centre, cross-sectional, observational study enrolling consecutive PsA participants has been conducted from July 2021 to November 2021. The Disease Activity for Psoriatic Arthritis (DAPSA) was collected; the following formulation of PASS question: 'Think about all the ways your PsA has affected you during the last 48 hours. If you were to remain in the next few months as you were during the last 48 hours, would this be acceptable to you?', was submitted to our participants. RESULTS: Multivariable logistic regressions, adjusted for the presence of fibromyalgia, did not show any significant association between PASS and DAPSA low disease activity, DAPSA as nominal variable (remission, low disease activity, moderate disease activity, high disease activity) and DAPSA as continuous variable. CONCLUSIONS: Our data suggest that fibromyalgia influences the patient's perception of the disease and has a negative impact on PASS status independently of disease activity, thus limiting the utility of this Patient reported outcome in real world clinical practice.

The negative impact of pain catastrophising on disease activity: analyses of data derived from patient-reported outcomes in psoriatic arthritis and axial spondyloarthritis.

OBJECTIVES: Psychosocial factors are recognised as important determinants of pain experience in patients with inflammatory arthritides. Among them, pain catastrophising, a maladaptive cognitive style, observed in patients with anxiety and depressive disorders, garnered specific attention. Here, we evaluated pain catastrophising (PC) and its related domains (Rumination, Magnification, and Helplessness), in psoriatic arthritis (PsA) and axial spondyloarhtiritis (axSpA) participants, to assess its impact on disease activity. Furthermore, we analysed possible correlations of PC-Scale (PCS) with those psychometric domains which have been already related to catastrophisation in patients with chronic pain. Lastly, we aimed to define the relationship between PCS and the different variables included in the composite indices of disease activity. METHODS: A multi-centre, cross-sectional, observational study has been conducted on 135 PsA (age 56 (47-64) years, males/females 40.74/59.26%; Disease Activity in Psoriasic Arthritis (DAPSA) 13.34 (5.21-22.22)) and 71 axSpA (age 49 (37-58) years, males/females 56.34/43.66%; Bath Ankylosing Spondylitis Arthritis Activity (BASDAI) 4.17 (2.1-6.3)) participants. Multivariable regressions and correlations were performed to evaluate the relationship between pain catastrophising and both disease activity and patient-reported outcomes. RESULTS: The adjusted linear regression model showed a positive association between PCS and DAPSA as well as between PCS and BASDAI; PCS negative impacts on the subjective domains of disease activity scores. CONCLUSIONS: This study suggests the role of PC, independently of inflammation, in disease perception and achievement of remission or low disease activity in chronic arthritides.

The hyper-expression of NLRP4 characterizes the occurrence of macrophage activation syndrome assessing STING pathway in adult-onset Still's disease.

To assess stimulator of interferon genes (STING) pathway in patients with adult-onset Still's disease (AOSD) who were complicated or not by macrophage activation syndrome (MAS), evaluating peripheral blood mononuclear cells (PBMCs), and synovial tissues. The relative mRNA expression of key molecules of the STING pathway (i.e. CGAS, NLRP4, PKDC, STING1, XRCC5, and XRCC6) and interferon (IFN)-γ was assessed in PBMCs obtained from patients with AOSD, who were complicated or not by MAS, and healthy controls (HCs). A bulky RNA sequencing was performed in synovial tissues from two patients with AOSD. Finally, the ability of heavy ferritin subunit (FeH) to induce the expression of NLRP4 was evaluated in cultured macrophages. Twenty patients with AOSD were analysed. Out of them, seven patients were complicated by MAS. Assessing mRNA relative expression in PBMCs, STING1, NLRP4, XRCC6, and IFN-γ were significantly expressed in AOSD than HCs. The mRNA relative expression of CGAS, PKDC, and XRCC5 did not differ between patients and HCs. Furthermore, NLRP4 and IFN-γ resulted to be significantly increased in patients with AOSD complicated by MAS than others. By RNA-sequencing analysis, we observed that Nlrp4 gene was significantly up-regulated in patients with AOSD. Following the stimulation with FeH, an increased expression of NLRP4 was observed in cultured macrophages. In conclusion, an increased expression of some key molecules of STING pathway characterized patients with AOSD. In addition, our results suggested that a hyper-activity of NLRP4 may be observed in patients with MAS. Furthermore, FeH increased the expression of NLRP4 in cultured macrophages.

Cytokine profile, ferritin and multi-visceral involvement characterize macrophage activation syndrome during adult-onset Still's disease.

OBJECTIVES: To multidimensionally characterize macrophage activation syndrome (MAS) complicating adult-onset Still's disease (AOSD) considering cytokine profile, inflammatory markers and multi-visceral involvement of the disease. To perform a high-dimensional phenotypic analysis of circulating immune cells in AOSD patients with and without MAS. To assess interferon (IFN)-related pathways in AOSD synovial tissues by a bulky RNA sequencing. METHODS: Clinical and biologic data were collected and compared in AOSD patients with and without MAS. Sera biomolecules were analysed by Luminex multiplexing technology. Mass cytometry (CyTOF) was used to characterize circulating immune cells. A bulky RNA sequencing was performed in AOSD synovial tissues. RESULTS: Forty consecutive AOSD patients were assessed, 14 complicated with MAS. Paralleling with increases of systemic score and ferritin, MAS patients showed higher levels of IL-1α, IL-1ß, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-17A, IFN-γ, G-CSF, MCP-1, MIP-1α and SCF. Combining the discriminatory ability of these data in identifying MAS, the best model was composed by systemic score, ferritin, IFN-γ and IL-10. By CyTOF analysis, MAS patients showed an increase of circulating 'classical monocytes' and a reduction of total NK cells. Our assessment showed 3477 IFN-related genes (IRGs) were differently expressed in AOSD synovial tissues. CONCLUSIONS: A multidimensional characterization of AOSD patients suggested that IFN-γ, IL-10, ferritin and systemic score discriminated the occurrence of cytokine storm syndrome associated with MAS. The inflammatory milieu of AOSD and MAS may be related to a signature of circulating immune cells. Finally, our results about IRGs reinforced the role of IFN-γ in these patients.

Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease.

OBJECTIVE: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD). METHODS: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. RESULTS: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. CONCLUSION: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

Duration of clinical remission and low disease activity impacts on quality of life and its domains in psoriatic arthritis patients: results from an Italian multicentre study.

OBJECTIVES: Long-term quality of life (QoL) is significantly compromised in patients with psoriatic arthritis (PsA) and only partially improves achieving remission or low disease activity. The main aim of this study is to evaluate the QoL in PsA patients and to investigate their possible relationship with clinical remission and low disease activity, and with its duration over time. METHODS: A multicentre cross-sectional observational study has been performed. QoL domains considered were analysed through PROs. Chi2 test was used for analysis of contingency tables, while Mann-Whitney test and Kruskal-Wallis test with Holm's pairwise comparison corrections were used to compare ranks. To evaluate variables associated to the different QoL domains, univariate and multiple linear regressions were used. RESULTS: 143 participants were included in this study. The physical component of the Short Form-36 or Functional Assessment of Chronic Illness Therapy-Fatigue tends to improve with short duration of low or minimal disease activity. However, this is not confirmed for the mental component of SF-36 (MCS), which improved only with longer duration of low/minimal disease activity. CONCLUSIONS: This study proves the existence of an inverse relation between disease activity and QoL domains. Apart from low or minimal disease activity, also its persistence over time has a great influence on the patient's perception of their clinical condition; therefore, persistence over time of clinical remission/low disease activity should be added to the latest definition of treat-to-target in PsA.

The role of stroma and epithelial cells in primary Sjögren's syndrome.

Primary SS (pSS) is a chronic autoimmune condition characterized by infiltration of the exocrine glands and systemic B cell hyperactivation. This glandular infiltration is associated with loss of glandular function, with pSS patients primarily presenting with severe dryness of the eyes and mouth. Within the affected glands, the infiltrating lymphocytes are organized in tertiary lymphoid structures. Tertiary lymphoid structures subvert normal tissue architecture and impact on organ function, by promoting the activation and maintenance of autoreactive lymphocytes. This review summarizes the current knowledge about the role of stromal cells (including endothelium, epithelium, nerves and fibroblasts) in the pathogenesis of pSS, in particular the interactions taking place between stromal cells and infiltrating lymphocytes. We will provide evidences pointing towards the driving role of stromal cells in the orchestration of the local inflammatory milieu, thus highlighting the need for therapies aimed at targeting this compartment alongside classical immunosuppression in pSS.

Dissecting the clinical heterogeneity of adult-onset Still's disease: results from a multi-dimensional characterization and stratification.

OBJECTIVES: To stratify adult-onset Still's disease (AOSD) patients in distinct clinical subsets to be differently managed, by using a multi-dimensional characterization. METHODS: AOSD patients were evaluated by using a hierarchical unsupervised cluster analysis comprising age, laboratory markers systemic score and outcomes. The squared Euclidean distances between each pair of patients were calculated and put into a distance matrix, which served as the input clustering algorithm. Derived clusters were descriptively analysed for any possible difference. RESULTS: Four AOSD patients clusters were identified. Disease onset in cluster 1 was characterized by fever (100%), skin rash (92%) and arthritis (83%), with the highest ferritin levels [mean (S.D.) 14 724 (6837) ng/ml]. In cluster 2, the onset was characterized by fever (100%), arthritis (100%) and liver involvement (90%), together with the highest CRP levels [288.10 (46.01) mg/l]. The patients in cluster 3 presented with fever (100%), myalgia (96%) and sore throat (92%). The highest systemic score values [8.88 (1.70)] and the highest mortality rate (54.2%) defined cluster 3. Fever (100%) and arthritis (90%) were the symptoms at the onset in cluster 4, which was characterized by the lowest ferritin and CRP levels [1457 (1298) ng/ml and 54.98 (48.67) mg/l, respectively]. CONCLUSION: Four distinct phenotypic subgroups in AOSD could be suggested, possibly associated with different genetic background and pathogenic mechanisms. Our results could provide the basis for a precision medicine approach in AOSD in an attempt to find a clinical and laboratory multidimensional stratification and characterization, which would drive a tailored therapeutic approach in these patients.

Benefits of anakinra versus TNF inhibitors in rheumatoid arthritis and type 2 diabetes: long-term findings from participants furtherly followed-up in the TRACK study, a multicentre, open-label, randomised, controlled trial.

OBJECTIVES: Interleukin (IL)-1ß is considered a shared pathogenic mediator between rheumatoid arthritis (RA) and type 2 diabetes (T2D). In the TRACK study, participants with both diseases were randomised to an IL-1 inhibitor, anakinra, or a TNF inhibitor (TNFi). After 6 months, anakinra induced a such of improvement on metabolic and inflammatory parameters, leading to a premature stoppage of the study. Thus, we aimed to assess how long IL-1 inhibition benefits lasted. METHODS: Since the TRACK was prematurely discontinued for "early benefit", we furtherly followed-up the enrolled participants to assess how long persisted the improvement of glycated haemoglobin (HbA1c%) and of RA disease activity. RESULTS: After a mean follow-up of 18 months (15 participants in anakinra-group and 14 in TNFi-group), RA clinical response was retained in both groups (DAS28: 2.59±1.01 vs. 2.88±0.91; p=0.109). Concomitant glucocorticoids were reduced in both groups (2.01±0.71 vs. 3.01±0.87 mg/die; p=0.124), but a larger percentage of anakinra-treated participants discontinued such drugs (53.3% vs. 28.6%; p=0.004). There was no difference between anakinra and TNFi for HbA1c% (6.60±0.52 vs. 6.79±0.43; p=0.291), but a reduction of anti-diabetic drugs was observed in anakinra-treated participants (53.3% vs. 7.1%; p=0.008) whereas an increase of anti-diabetic therapies was needed in TNFi-treated ones. Significant correlations were also observed among HbA1c% with DAS28 and with C-reactive protein. Analysing the safety profile, only minor side effects were recorded. CONCLUSIONS: Data deriving from the long-term extension of participants with RA and T2D, enrolled in the TRACK study, could suggest that the benefits of IL-1 inhibition on metabolic and inflammatory parameters could last longer than first 6 months of follow-up, but further studies are needed to confirm these findings.

Lung involvement in macrophage activation syndrome and severe COVID-19: results from a cross-sectional study to assess clinical, laboratory and artificial intelligence-radiological differences.

OBJECTIVES: To evaluate the clinical pictures, laboratory tests and imaging of patients with lung involvement, either from severe COVID-19 or macrophage activation syndrome (MAS), in order to assess how similar these two diseases are. METHODS: The present work has been designed as a cross-sectional single-centre study to compare characteristics of patients with lung involvement either from MAS or severe COVID-19. Chest CT scans were assessed by using an artificial intelligence (AI)-based software. RESULTS: Ten patients with MAS and 47 patients with severe COVID-19 with lung involvement were assessed. Although all patients showed fever and dyspnoea, patients with MAS were characterised by thrombocytopaenia, whereas patients with severe COVID-19 were characterised by lymphopaenia and neutrophilia. Higher values of H-score characterised patients with MAS when compared with severe COVID-19. AI-reconstructed images of chest CT scan showed that apical, basal, peripheral and bilateral distributions of ground-glass opacities (GGOs), as well as apical consolidations, were more represented in severe COVID-19 than in MAS. C reactive protein directly correlated with GGOs extension in both diseases. Furthermore, lymphopaenia inversely correlated with GGOs extension in severe COVID-19. CONCLUSIONS: Our data could suggest laboratory and radiological differences between MAS and severe COVID-19, paving the way for further hypotheses to be investigated in future confirmatory studies.

Mortality in tocilizumab-treated patients with COVID-19: a systematic review and meta-analysis.

OBJECTIVES: People who are exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could develop a potentially fatal disease with lung involvement and severe cytokine storm syndrome (CSS) - coronavirus disease 2019 (hereafter, COVID-19). Tocilizumab (TCZ) was administered to these subjects, despite the lack of randomised clinical trial data. Hence, summarising data on the mortality rate and related risks factors may help physicians to correctly administer TCZ. METHODS: We performed a systematic review and meta-analysis on mortality rate in TCZ- treated patients with COVID-19 according to the PRISMA guidelines. The pooled mortality rate in TCZ-treated persons was calculated and meta-regressions were done to investigate associated factors. RESULTS: We included 22 studies and 1520 TCZ-treated patients (mean age: 61 years, 95% CI: 59-64; male: 71%, 95% CI: 64-78%). The mortality estimated pooled prevalence was 19% (95% CI: 13-25, I2=100%, p<0.00001) and improvement estimated pooled prevalence was 71% (95% CI: 62-81). Factors associated with the mortality are the number of patients in intensive care unit, the number of patients requiring invasive ventilation and the sera C-reactive protein value before TCZ administration. We observed a reduction in the odds of mortality in TCZ-treated patients when compared to those treated with other therapies (OR=0.47, 95% CI: 0.22-0.98, p=0.004). CONCLUSIONS: This study showed that the mortality pooled prevalence in TCZ-treated patients is lower than the overall mortality reported in patients with severe COVID-19.

Italian recommendations for influenza and pneumococcal vaccination in adult patients with autoimmune rheumatic diseases.

OBJECTIVES: To provide evidence-based recommendations for vaccination against influenza virus and S. pneumoniae in patients with autoimmune rheumatic diseases (ARDs). METHODS: A Consensus Committee including physicians with expertise in rheumatic and infectious diseases was established by two Italian scientific societies, Società Italiana di Reumatologia (SIR) and Società Italiana di Malattie Infettive e Tropicali (SIMIT). The experts were invited to develop evidence-based recommendations concerning vaccinations in ARDs patients, based on their clinical status before and after undergoing immunosuppressive treatments. Key clinical questions were formulated for the systematic literature reviews, based on the clinical pathway. A search was made in Medline (via PubMed) according to the original MeSH strategy from October 2009 and a keyword strategy from January 2016 up to December 2017, updating existing EULAR recommendations. Specific recommendations were separately voted and scored from 0 (no agreement with) to 100 (maximal agreement) and supporting evidence graded. The mean and standard deviation of the scores were calculated to determine the level of agreement among the experts' panel for each recommendation. Total cumulative agreement ≥70 defined consensus for each statement. RESULTS: Nine recommendations, based on 6 key clinical questions addressed by the expert committee, were proposed. The aim of this work is to integrate the 2011 EULAR recommendations on vaccination against influenza and S. pneumoniae in ARDs patients. An implementation plan was proposed to improve the vaccination status of these patients and their safety during immunosuppressive treatments. CONCLUSIONS: Influenza and pneumococcus vaccinations are effective and safe in patients with ARDs. More efforts should be made to translate the accumulated evidence into practice.

The role of extracellular matrix components in angiogenesis and fibrosis: Possible implication for Systemic Sclerosis.

Extracellular matrix (ECM) plays a crucial role in the regulation of both physiological and pathological angiogenesis. ECM homeostasis and function is ensuring by the tightly regulation of the different ECM components including, collagens, proteoglycans and a variety of different glycoproteins. An altered expression of the above ECM molecules as well as an imbalance between the action of matrix remodeling enzymes and their tissue inhibitors is known to be responsible for impaired angiogenesis and fibrosis. Systemic Sclerosis (SSc) is an autoimmune disease characterized by micro-angiopathy, failure of reparative angiogenesis, and excessive fibrosis of the skin and various internal organs, dues to an increased production of ECM. A comprehensive search through Medline/PubMed and Scopus was performed for English-language original papers, using the keywords related to ECM components and SSc. This review will analyze the role played by ECM components in the deregulation of angiogenic mechanisms and in the persistence of a pro-fibrotic phenotype, during SSc. A better knowledge of these processes might provide information about molecules, which could be considered targets for future pro-angiogenic and/or anti-fibrotic therapies.

Interstitial lung disease in systemic sclerosis: current and future treatment.

Systemic sclerosis (SSc) has the highest fatality rate among connective tissue diseases and is characterized by vascular damage, inflammation and fibrosis of the skin and various internal organs. Interstitial lung disease (ILD) frequently complicates SSc and can be a debilitating disorder with a poor prognosis. ILD is the most frequent cause of death in SSc, and the management of SSc-ILD patients is a great challenge. Early detection of pulmonary involvement based on a recent decline of lung function tests and on the extent of lung involvement at high-resolution computed tomography is critical for the best management of these patients. This article summarizes classification, pathogenesis, diagnosis, prognosis, survival and finally current and future treatment options in SSc-ILD.

Adult-onset Still's disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers.

BACKGROUND: Adult-onset Still's disease (AOSD) is rare inflammatory disease of unknown etiology that usually affects young adults. The more common clinical manifestations are spiking fevers, arthritis, evanescent rash, elevated liver enzymes, lymphadenopathy, hepatosplenomegaly, and serositis. The multi-visceral involvement of the disease and the different complications, such as macrophage activation syndrome, may strongly decrease the life expectancy of AOSD patients. METHODS: This study aimed to identify the positive and negative features correlated with the outcome of patients. A retrospective analysis of AOSD patients prospectively admitted to three rheumatologic centers was performed to identify the clinical features present at the time of diagnosis and to predict the possible outcome. Furthermore, we investigated the as yet to be validated prognostic value of the systemic score previously proposed. RESULTS: One hundred consecutive AOSD patients were enrolled. The mean systemic score showed that the majority of patients had a multi-organ involvement. Sixteen patients showed different complications, mainly the macrophage activation syndrome. A strong increase of inflammatory markers was observed. All patients received steroids at different dosages, 55 patients in association with immunosuppressive drugs and 32 in association with biologic agents. Sixteen patients died during the follow-up. Regression analysis showed that the higher values of the systemic score and the presence of AOSD-related complications, assessed at the time of diagnosis, were significantly correlated with patient mortality. A prognostic impact of the systemic score of ≥ 7.0 was reported. CONCLUSIONS: Our study showed that a higher systemic score and the presence of AOSD-related complications at the time of diagnosis were significantly associated with mortality. Of note, a cut-off at 7.0 of the systemic score showed a strong prognostic impact in identifying patients at risk of AOSD-related death.

Mesenchymal stromal cells and rheumatic diseases: new tools from pathogenesis to regenerative therapies.

In recent years, mesenchymal stromal cells (MSCs) have been largely investigated and tested as a new therapeutic tool for several clinical applications, including the treatment of different rheumatic diseases. MSCs are responsible for the normal turnover and maintenance of adult mesenchymal tissues as the result of their multipotent differentiation abilities and their secretion of a variety of cytokines and growth factors. Although initially derived from bone marrow, MSCs are present in many different tissues such as many peri-articular tissues. MSCs may exert immune-modulatory properties, modulating different immune cells in both in vitro and in vivo models, and they are considered immune-privileged cells. At present, these capacities are considered the most intriguing aspect of their biology, introducing the possibility that these cells may be used as effective therapy in autoimmune diseases. Therefore, stem cell therapies may represent an innovative approach for the treatment of rheumatic diseases, especially for the forms that are not responsive to standard treatments or alternatively still lacking a definite therapy. At present, although the data from scientific literature appear to suggest that such treatments might be more effective whether administered as soon as possible, the use of MSCs in clinical practice is likely to be restricted to patients with a long history of a severe refractory disease. Further results from larger clinical trials are needed to corroborate preclinical findings and human non-controlled studies, and advancement in the knowledge of MSCs might provide information about the therapeutic role of these cells in the treatment of many rheumatic diseases.