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Background: Chronic pain and inflammation are common features of rheumatic conditions such as Psoriatic Arthritis (PsA) and Axial Spondyloarthritis (axSpA), often needing prolonged medication treatment for effective management. Maintaining drug retention is essential for both achieving disease control and improving patients' quality of life. This study investigates the influence of pain catastrophizing, a psychological response to pain, on the drug retention rates of PsA and axSpA patients., Methods: A two-year prospective multicenter observational study involved 135 PsA and 71 axSpA patients. Pain Catastrophizing Scale (PCS) was employed to assess pain catastrophizing. Univariable and multivariable regression analyses were utilized to identify factors associated with drug retention., Results: In the PsA group, patients early discontinuing therapy showed higher baseline disease activity as well as higher incidence of comorbid fibromyalgia. Notably, pain catastrophizing, specifically the domains of Helplessness, Magnification, and Rumination, were significantly elevated in PsA patients who interrupted the treatment. Multivariable analysis confirmed pain catastrophizing as an independent predictor of drug suspension within two years. In axSpA, drug discontinuation was associated with female gender, shorter disease duration, higher baseline disease activity as well as elevated levels of pain catastrophizing. Univariable analysis supported the role of pain catastrophizing, including its domains, as predictors of treatment interruption. However, limited events in axSpA patients precluded a multivariate analysis., Conclusion: This prospective study emphasizes the impact of pain catastrophizing on drug retention in patients with PsA and axSpA., (© 2024. The Author(s).)

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.

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest for this work., (Copyright © 2024. Published by Elsevier B.V.)

Objective: We aimed to evaluate the clinical usefulness of the systemic score in the prediction of life-threatening evolution in Still disease. We also aimed to assess the clinical relevance of each component of the systemic score in predicting life-threatening evolution and to derive patient subsets accordingly., Methods: A multicenter, observational, prospective study was designed including patients included in the Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale Adult-Onset Still Disease Study Group and the Autoinflammatory Disease Alliance Network Still Disease Registry. Patients were assessed to see if the variables to derive the systemic score were available. The life-threatening evolution was defined as mortality, whatever the clinical course, and/or macrophage activation syndrome, a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis., Results: A total of 597 patients with Still disease were assessed (mean ± SD age 36.6 ± 17.3 years; male 44.4%). The systemic score, assessed as a continuous variable, significantly predicted the life-threatening evolution (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.07-1.42; P = 0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life-threatening evolution (OR 3.36; 95% CI 1.81-6.25; P < 0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR 1.68; 95% CI 1.48-2.67; P = 0.031) and lung disease (OR 2.12; 95% CI 1.14-4.49; P = 0.042) both significantly predicted life-threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations., Conclusion: The clinical utility of the systemic score was shown in identifying Still disease at a higher risk of life-threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted., (© 2024 American College of Rheumatology.)

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.

Background: Psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are inflammatory diseases with shared genetic backgrounds and clinical comorbidities. Headache, a common global health issue, affects over 50% of adults and encompasses various types, including migraine, tension-type, and cluster headaches. Migraine, the most prevalent, recurrent, and disabling type, is often associated with other medical conditions such as depression, epilepsy, and psoriasis, but little is known about the relationship between autoimmune disease and the risk of migraine., Methods: A cross-sectional study was conducted from July to November 2022, enrolling 286 participants, including 216 with PsA, 70 with axSpA, and 87 healthy controls., Results: Headache prevalence was significantly higher in the PsA (39.81%) and axSpA (45.71%) patients compared to the healthy controls. The prevalence of migraine without aura was also significantly higher in both the PsA (18.52%) and axSpA (28.57%) groups compared to the healthy controls., Conclusions: These findings underscore the high burden of headache and migraine in PsA and axSpA participants, highlighting the need for improved management and treatment strategies for these patients.

Sjӧgren's disease (SjD) is a systemic autoimmune disorder characterized by the chronic inflammation and dysfunction of exocrine glands, mainly salivary glands, causing dryness of the eyes and of the mouth. The disease may affect different organs and tissues with complex and heterogeneous clinical presentation, usually with sicca symptoms, profound fatigue, chronic pain, major organ involvement, and lymphomas. SjD diagnosis is based on the combination of clinical, serological, and functional tests with histological biomarkers. Minor salivary gland biopsy (mSGB) represents the cornerstone for the diagnosis of SjD, allowing the study of the characteristic focal infiltration of B- and T lymphocytes. Besides, mSGB might also have a prognostic role, being the infiltrates more complex in patients with severe SjD. But biopsy, so far, is not mandatory for SjD and mSG ultrasound and peripheral biomarkers might replace its role in the future. Another important aspect of SjD is the presence of autoantibodies, although 20 to 30% of patients are "seronegative" for specific autoantibodies (ANA, antiRo/SSA, antiLa/SSB). The characteristics of this subset of patients are currently under evaluation and "new" autoantibodies and biomarkers might be necessary for better patient's stratification and follow-up., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Still's disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still's disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still's disease., Methods: Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still's disease., Results: A total of 411 patients suffering from Still's disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still's disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments., Conclusions: Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still's disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still's disease is the same clinical condition arising in different ages., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Atlantoaxial joint is a possible affected site during rheumatoid arthritis (RA) and, in this work, we evaluated its occurrence and associated characteristics in a "real-life" cohort. By a medical records review study of RA patients longitudinally followed-up, the occurrence of severe atlantoaxial joint involvement was estimated (incidence proportion and incidence rate per 1000 person-years at risk). Regression analyses were also exploited to evaluate possible associated factors. Based on these findings, a prospective recruitment was performed to build a descriptive cross-sectional study in evaluating a subclinical atlantoaxial joint involvement in patients with the same clinical characteristics. Retrospectively, 717 patients (female 56.6%, age 64.7 ± 12.3 years) were studied. The incidence proportion of severe atlantoaxial joint involvement was 2.1% [1.5-2.5], occurring in 15 out of 717 patients, and identified by both MRI and CT scan. Considering over 3091 person-years, an incidence rate of 5.2 × 1000 [2.9-8.3] person-years was estimated. Regression analyses suggested that male gender, a longer disease duration, ACPA positivity and extra-articular manifestations resulted to be significantly associated with a severe atlantoaxial joint involvement. Given these findings, 30 asymptomatic patients were selected according to these clinical characteristics and underwent MRI of cervical spine. To date, almost 50% of these asymptomatic patients showed a subclinical atlantoaxial joint involvement. The occurrence of the severe atlantoaxial joint involvement in RA patients was estimated in a "real-life" setting. Male gender, ACPA positivity, long disease duration, and extra-articular manifestations could be associated with the severe atlantoaxial joint involvement in RA. MRI could provide a useful clinical tool to early evaluate the atlantoaxial joint involvement in RA, also in asymptomatic patients., (© 2023. The Author(s).)

Background: Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients., Methods: Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters., Results: K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients., Conclusions: Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', 'Uncomplicated', 'Hyperferritinemic' and 'Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

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.

Objectives: Aim of this study was to investigate the expression of interleukin (IL)-40, a new cytokine associated with B cells homoeostasis and immune response, in primary Sjögren syndrome (pSS) and in pSS-associated lymphomas., Methods: 29 patients with pSS and 24 controls were enrolled. Minor salivary gland (MSG) biopsies from patients, controls and parotid gland biopsies from pSS-associated lymphoma were obtained. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-40 were performed on MSG. MSG cellular sources of IL-40 were determined by flow-cytometry and immunofluorescence. Serum concentration of IL-40 was assessed by ELISA and cellular sources of IL-40 were determined by flow-cytometry. An in vitro assay with recombinant IL-40 (rIL-40) was performed to detect the effect on cytokine production from peripheral blood mononuclear cells (PBMCs)., Results: IL-40 was significantly increased in the lymphocytic infiltrated MSG of patients with pSS and correlated with focus score and with IL-4 and transforming growth factor-β expression. In addition, IL-40 was increased in the serum of pSS and its levels correlated with the EULAR Sjögren's Syndrome Disease Activity Index score. B cells from patients were shown to be the major source of IL-40 at both tissue and peripheral level. PBMCs from patients, exposed to rIL-40 in vitro, released proinflammatory cytokines, specifically interferon-γ from B cells and T-CD8 + and tumour necrosis factor-α and IL-17 from both T-CD4 + and T-CD8 + . IL-40 expression in parotid glands of pSS-associated lymphomas was also increased. Moreover, IL-40-driven NETosis was evidenced in neutrophils obtained from pSS., Conclusion: Our results suggest that IL-40 may play a role in pSS pathogenesis and pSS-associated lymphomas., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: COVID-19 and autoinflammatory diseases, such as Adult-onset Still's Disease (AOSD), are characterized by hyperinflammation, in which it is observed massive production and uncontrolled secretion of pro-inflammatory cytokines. The specialized pro-resolving lipid mediators (SPMs) family is one the most important processes counteracting hyperinflammation inducing tissue repair and homeostasis restoration. Among SPMs, Protectin D1 (PD1) is able to exert antiviral features, at least in animal models. The aim of this study was to compare the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with AOSD and COVID-19 and to evaluate the role of PD1 on those diseases, especially in modulating macrophages polarization., Methods: This study enrolled patients with AOSD, COVID-19, and healthy donors HDs, undergoing clinical assessment and blood sample collection. Next-generation deep sequencing was performed to identify differences in PBMCs transcripts profiles. Plasma levels of PD1 were assessed by commercial ELISA kits. Monocyte-derived macrophages were polarized into M1 and M2 phenotypes. We analyzed the effect of PD1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays., Results: In the transcriptomes from AOSD patients and COVID-19 patients, genes involved in inflammation, lipid catabolism, and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Patients affected by COVID-19, hospitalized in intensive care unit (ICU), showed higher levels of PD1 when compared to not-ICU hospitalized patients and HDs (ICU COVID-19 vs not-ICU COVID-19, p= 0.02; HDs vs ICU COVID-19, p= 0.0006). PD1 levels were increased in AOSD patients with SS ≥1 compared to patients with SS=0 (p=0.028) and HDs (p=0.048). In vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p<0.05). Furthermore, a significant release of IL-10 and MIP-1β from M2 macrophages was observed when compared to controls (p<0.05)., Discussion: PD1 is able to induce pro-resolutory programs in both AOSD and COVID-19 increasing M2 polarization and inducing their activity. In particular, PD1-treated M2 macrophages from AOSD and COVID-19 patients increased the production of IL-10 and enhanced homeostatic restoration through MIP-1β production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Navarini, Vomero, Currado, Berardicurti, Biaggi, Marino, Bearzi, Corberi, Rigon, Arcarese, Leuti, Fava, Fogolari, Mattei, Ruscitti, Di Cola, Sambuco, Travaglino, Angeletti, Ursini, Mariani, Cipriani, Agrò, Iagnocco, Antonelli Incalzi, Maccarrone and Giacomelli.)

Background: Pulmonary lung involvement is the most common extra-glandular manifestation in patients with primary Sjögren's syndrome (pSS), leading to a worsening of the patient's prognosis. To date, different studies have assessed the prevalence of pulmonary involvement and interstitial lung disease (ILD) in pSS patients with different results., Methods: We performed a systematic literature review and meta-analysis on ILD pooled prevalence in pSS according to the PRISMA and MOOSE guidelines. Furthermore, we explored the pooled prevalence of the two main presentations of pSS-ILD, nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP)., Results: We analysed the pSS-ILD prevalence in 30 studies including 8255 pSS patients. The pSS-ILD pooled prevalence was 23% (95% CI: 16-30). For NSIP, we found a pooled prevalence of 52% (CI 41-64), and for UIP we found a pooled prevalence of 44% (CI: 32-55). Regarding the meta-regression analysis, male gender, DLco value, country, and HRCT seem to contribute to the ILD presence., Conclusions: At least 20% of pSS patients have a comorbid ILD, usually NSIP. Male gender and alteration in DLco value may be considered the most important independent factors supporting an active search of lung complications during the clinical history of pSS patients.

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-1β, 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background : the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a pivotal role in immune cells regulation. The plasma levels of 2-AG are increased in patients with systemic lupus erythematosus (SLE) and correlate with disease activity. Moreover, in plasmacytoid dendritic cells from SLE patients, 2-AG is able to control the production of type 1 interferon (IFN) through CB 2 activation. The aim of this study was to evaluate the potential role of 2-AG on T lymphocytes from SLE patients. Methods : peripheral blood mononuclear cells (PBMCs) from SLE participants and age- and sex-matched healthy donors (HD) were isolated by Ficoll-Hypaque density-gradient centrifugation. The PBMCs were treated with increasing concentrations of 2-AG, and AM251 and AM630 were used to antagonize CB 1 and CB 2, respectively. Flow cytometry was used to assess the expression of CD3, CD4, CD8, CD25, IFN-ɣ, IL-4, and IL-17A. Results : 2-AG (1 μM) decreased IFN-ɣ expression ( p = 0.0005) in the Th1 lymphocytes of SLE patients. 2-AG did not modulate the cytokine expression of any other T lymphocyte population from either SLE or HD. Treatment with both 2-AG and AM630 increased the IFN-ɣ expression in Th1 lymphocytes of SLE patients ( p = 0.03). Discussion : 2-AG is able to modulate type 2 IFN production from CD4+ T lymphocytes from SLE patients through CB 2 activation.

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.

During rheumatoid arthritis (RA), the pathogenic role of resident cells within the synovial membrane is suggested, especially for a population frequently referred to as fibroblast-like synoviocytes (FLSs). In this study, we assess the markers of myofibroblast differentiation of RA-FLSs by ex vivo observations and in vitro evaluations following the stimulation with both TGF-β and IL-6. Furthermore, we investigated the possible inhibiting role of tofacitinib, a JAK inhibitor, in this context. Myofibroblast differentiation markers were evaluated on RA synovial tissues by immune-fluorescence or immune-histochemistry. RA-FLSs, stimulated with transforming growth factor (TGF-β) and interleukin-6 (IL-6) with/without tofacitinib, were assessed for myofibroblast differentiation markers expression by qRT-PCR and Western blot. The same markers were evaluated following JAK-1 silencing by siRNA assay. The presence of myofibroblast differentiation markers in RA synovial tissue was significantly higher than healthy controls. Ex vivo, α-SMA was increased, whereas E-Cadherin decreased. In vitro, TGF-β and IL-6 stimulation of RA-FLSs promoted a significant increased mRNA expression of collagen I and α-SMA, whereas E-Cadherin mRNA expression was decreased. In the same conditions, the stimulation with tofacitinib significantly reduced the mRNA expression of collagen I and α-SMA, even if the Western blot did not confirm this finding. JAK-1 gene silencing did not fully prevent the effects of stimulation with TGF-β and IL-6 on these features. TGF-β and IL-6 stimulation may play a role in mediating myofibroblast differentiation from RA-FLSs, promoting collagen I and α-SMA while decreasing E-Cadherin. Following the same stimulation, tofacitinib reduced the increases of both collagen I and α-SMA on RA-FLSs, although further studies are needed to fully evaluate this issue and confirm our results.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An accurate prediction of cardiovascular (CV) risk in patients with Axial Spondyloarthritis (axSpA) is a strong unmet need, as CV risk algorithms poorly perform in these subjects. The aim of this study was to establish whether the persistence of high C-reactive protein (CRP) and high disease activity may be considered predictive factors of CVD in axSpA. 295 patients without personal history of CVD, were consecutively enrolled in this study. To evaluate the relationship between CV events occurrence (fatal and non-fatal) and the persistence of increased CRP levels, ASDAS (Ankylosing Spondylitis Disease Activity Score) > 2.1, and BASDAI (Bath Ankylosing Spondylitis Disease Activity) > 4 during the follow-up, univariable and multivariable Cox Proportional Hazard Models have been performed. During follow-up (we analyzed 10-years retrospective data), 23 patients had a CV event. Multivariable Cox Proportional Hazard Models showed a strong association between CV event and the persistency of increased CRP levels (namely, percentage of visits in which CRP levels were increased) (HR = 1.03; 95%CI 1.015-1.045; p < 0.001), of ASDAS > 2.1 (HR = 1.014, 95%CI 1.000-1.028, p = 0.047), and of BASDAI > 4 (HR 1.019, 95%CI 1.006-1.033, p = 0.006) during follow-up, after adjustment for age, sex, and diabetes. This study suggests that persistence of increased CRP levels and high disease activity may be considered biomarkers to identify those axSpA patients at higher risk of CVD. Innovative axSpA-specific CV risk score, including these variables, have to be developed., (© 2022. The Author(s).)

Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans., (© 2022. The Author(s).)

Objective: Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS., Methods: Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation., Results: SGECs from primary SS patients (n = 24) exhibited increased autophagy (autophagic flux [P = 0.001]; LC3-IIB [P = 0.02]; p62 [P = 0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P = 0.006]), and reduced apoptosis (annexin V/PI [P = 0.002]; caspase 3 [P = 0.057]), compared to samples from patients with sicca syndrome (n = 16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy., Conclusion: In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target., (© 2021 American College of Rheumatology.)

Systemic sclerosis (SSc) is an uncommon autoimmune disease. Aim of the study was to detect the occult cardiac involvement in asymptomatic SSc patients of recent onset (indicative of a more aggressive disease) with unenhanced Cardiac Magnetic Resonance (CMR). Our historical prospective study included naïve SSc patients of recent onset. Modified Rodnan Skin Score (mRSS) and Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) were calculated. Cardiac volumes and global myocardial strain were assessed and also compared with healthy group values. Pericardial involvement was further recorded. Thirty-one patients met inclusion criteria (54 ± 12 years; 1 M). Mean duration of disease was 6.8 years. All patients showed preserved systolic function. Higher incidence of pericardial involvement was founded in patients with disease accrual damage (OR: 9.6, p-value 0.01). Radial and longitudinal strain values resulted significantly different between healthy and SSc patients. GRS and GLS showed an independent predictive validity on damage accrual (HR: 1.22 and 1.47, respectively). Best C-index for disease progression was reached when strain values and pericardial evaluation were added to conventional risk factors (0.97, p-value: 0.0001). Strain analysis by CMR-TT may show a high capability both in identifying early cardiac involvement and stratifying its clinical aggressiveness, regardless of the standard damage indices and CMR contrast-dependent biomarker., (© 2022. The Author(s).)

The objective of this study is to describe the possible prognostic impact of smoking habit on adult-onset Still's disease (AOSD) patients, by the assessment of clinical characteristics, life-threatening complications occurrence, and mortality in smokers than non-smokers. A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was conducted. Out of 185 AOSD assessed patients, 45 smokers were identified. These showed a higher frequency of pericarditis (35.5% vs 16.4%, p = 0.011), pleuritis (33.3% vs 14.3%, p = 0.008), and abdominal pain (17.7% vs 6.4%, p = 0.035). Furthermore, smokers showed higher values of systemic score (6.4 ± 2.2 vs 5.4 ± 1.8, p = 0.004), an increased rate of macrophage activation syndrome (MAS) (28.9% vs 6.4%, p < 0.0001) and of parenchymal lung disease (17.7% vs 12.6%, p = 0.035). Although not significant, these patients more frequently experienced a poor prognosis (13.3% vs 4.3%, p = 0.074). Smoking habit predicted MAS occurrence in both univariate (HR: 5.98, 95% CI: 2.45-14.57, p < 0.0001) and multivariate regression models (HR: 6.21, 95% CI: 2.46-15.70, p < 0.0001). Smokers had a significant higher risk of parenchymal lung disease in both univariate (HR: 3.97, 95% CI: 1.43-11.02, p = 0.008) and multivariate regression models (HR: 3.90, 95% CI: 1.36-11.23, p = 0.012). Smoking habit also increased the risk of mortality in univariate regression model (HR: 4.25, 95% CI: 1.33-13.55, p = 0.015). Smoking habit resulted to be a negative prognostic factor on AOSD patients. Smokers were characterised by a higher frequency of serositis and higher values of systemic score. Additionally, these patients were more frequently burdened by MAS and parenchymal lung disease associated with a poor prognosis. Key points • Smoking habit resulted to be a negative prognostic factor on AOSD. • Smokers were characterised by an increased frequency of serositis and higher values of systemic score. • Cigarette exposure was associated with MAS and parenchymal lung disease in AOSD., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objective: This work aims to evaluate the long-term safety of rituximab (RTX) in primary Sjögren syndrome (pSS) and to determine the safety and the efficacy of long-term treatment with B cell depleting therapy in pSS patients with active systemic disease., Methods: A historical cohort study, enrolling 35 patients with pSS treated with RTX between 2008 and 2019 in a single rheumatologic unit, was performed. When patients experienced adverse events, the treatment was suspended and patients' data were recorded., Results: The included patients were mainly female (91%), with a mean age of 54 years. During the time of observation, 13 patients (37.1%) suspended RTX treatment (10 cases per 100 patient-years, 95% CI 0.06-0.17). Baseline demographics, disease characteristics, European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) values, and treatment were comparable across RTX-suspended and nonsuspended groups. Patients exposed to RTX had been followed for 35.82 ± 32.56 months, and the time of observation varied from 6 to 96 months. All the patients except one experienced a significant and persisting meaningful improvement of their ESSDAI (≥ 3 points) during the long-term follow-up. For the duration of the follow-up, 13 (37%) patients discontinued RTX treatment. Four out of 13 (30.8%) discontinued the treatment after the first administration due to infusion-related reactions. During subsequent RTX courses, the main cause of withdrawal was hypogammaglobulinemia onset (7 patients). In 2 patients, hypogammaglobulinemia was associated with severe infections., Conclusion: Long-term RTX administration was shown to be a safe, well tolerated, and effective treatment in patients with active systemic disease, significantly reducing ESSDAI and controlling disease activity., (© 2022 by the Journal of Rheumatology.)

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., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In this study, we aimed at describing the multivisceral involvement on adult-onset Still's disease (AOSD) to retrieve imaging-based differences in patients with and without macrophage activation syndrome (MAS). From our historical cohort, patients were assessed among those who underwent a total body CT scan. Clinical and CT scan characteristics of AOSD patients with and without MAS were compared. Out of 39 AOSD patients evaluated, 14 were complicated by MAS. These patients showed higher values of ferritin and systemic score. AOSD patients with MAS presented a higher prevalence of lung disease, hepatomegaly, splenomegaly, abdominal effusions, and lymph node enlargement than others without this complication. In addition, the presence of these manifestations significantly correlated with the systemic score, furtherly reinforcing its prognostic value. Due to the specific design of our study, our findings could be burdened by a selection bias since assessing those patients underwent a total body CT scan. Thus, these data should be prudently generalised suggesting the need of further studies to fully elucidate this issue. Our findings showed a higher prevalence of multiorgan involvement in AOSD patients with MAS, suggesting imaging-based differences, although other studies are needed to fully assess this issue. Pulmonary disease, hepatomegaly, splenomegaly, lymph node enlargement, and abdominal effusions were associated with a more aggressive subset of AOSD. Key Points •The importance of an accurate assessment AOSD multivisceral involvement is suggested since it is associated with life-threatening complications. •A higher prevalence of multiorgan involvement in AOSD patients with MAS could be recognised, than others without this complication, suggesting imaging-based differences. •AOSD multivisceral involvement may correlate with the systemic score, furtherly reinforcing its prognostic value., (© 2021. International League of Associations for Rheumatology (ILAR).)

Abstract: Rheumatoid arthritis (RA) is associated with an increased risk of venous thromboembolism (VTE) occurrence. In this work, we assessed the incidence and predictive factors of VTE in our "real-life" cohort of RA patients. To contextualize our results, we reviewed the available literature about this topic.We performed a retrospective analysis of prospectively followed-up patients with RA attending our Rheumatologic Clinic between January 2010 and December 2020. Each patient was investigated for VTE occurrence. Incident cases were reported as incidence proportion and incidence rate per 1000 person-years at risk. Possible predictive factors were also exploited by regression analyses. Available literature about this topic was also assessed.In this evaluation, 347 consecutive patients without previous evidence of VTE, attending our Rheumatologic Clinic from 2010 to 2020, were studied. In our "real-life" cohort, the incidence proportion of VTE was 3.7% (2.7-4.7%) and considering over 1654 person-years, an incidence rate of 7.8 × 1000 (2.5-11.7). Exploratively assessing predictive factors in our cohort, older age (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.01-1.14, p = .015), higher body mass index (HR 1.37, 95% CI 1.04-1.80, P = .026), and longer disease duration (HR 1.11, 95% CI 1.03-1.20, P = .006) resulted to be significant predictors of VTE occurrence during the follow-up.In our "real-life" cohort, VTE burden has been suggested in patients with RA. Comparing our results with previous data derived from randomized controlled trials and administrative data, some different findings were retrieved about incidence of VTE. Assessing predictive factors, older age, higher body mass index, and longer disease duration resulted to be significant predictors of VTE occurrence during the follow-up. Taking together these observations, a further evaluation of this issue on specific designed studies is needed to provide more generalizable results to the daily clinical practice., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: During rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA., Methods: After ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated., Results: The expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib., Conclusions: We explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity., (© 2021. The Author(s).)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Adult onset Still's disease (AOSD) is a rare systemic autoinflammatory disease, characterised by fever, arthritis, and skin rash, and joint involvement is one of its clinical manifestations. The aims of this work were to assess joint involvement, to describe main patterns of involvement, and associated clinical characteristics. In this work, we aimed at assessing the joint involvement in AOSD by using MRI, to describe main patterns and associated clinical characteristics. In addition, we aimed at assessing the global transcriptomic profile of synovial tissues in AOSD to elucidate possible pathogenic pathways involved. We also evaluated the global transcriptomic profile of synovial tissues to elucidate possible pathogenic pathways involved in the disease. Thus, AOSD patients, who underwent to MRI exam on joints, were assessed to describe patterns of joint involvement and associated clinical characteristics. Some synovial tissues were collected for RNA-sequencing purposes. The most common MRI finding was the presence of synovitis on 60.5%, mainly in peripheral affected joints, with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. Bone oedema and MRI-bone erosions were reported on 34.9% and 25.6% MRI exams, respectively. Patients with MRI-bone erosions showed a higher prevalence of splenomegaly, a more frequent chronic disease course, lower levels of erythrocyte sedimentation rate, and ferritin. In AOSD synovial tissues, a hyper-expression of interleukin (IL)-1, IL-6, and TNF pathways was shown together with ferritin genes. In conclusion, in AOSD patients, the most common MRI-finding was the presence of synovitis, characterised by intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. MRI-bone erosions and bone oedema were also observed. In AOSD synovial tissues, IL-1, IL-6, and TNF pathways together with ferritin genes resulted to be hyper-expressed.

Objective: Patients with primary Sjögren's syndrome (pSS) may develop a potentially severe disease with extra-glandular involvement and lymphoma insurgence. Minor salivary gland biopsy is routinely used in the disease diagnosis, but its potential role as a biomarker for clinical disease presentation and prognosis is still poorly understood., Methods: We performed a systematic review and meta-analysis on clinical presentation and prognosis in pSS patients who underwent minor salivary gland biopsy at diagnosis according to the PRISMA guidelines., Results: We included five retrospective studies and 589 pSS patients. Ectopic GCs presence was not associated with a significant increase in the odds ratio for the clinical variables explored such as salivary gland swelling, arthritis, and Raynaud's phenomenon. As far as serological features are concerned, ectopic GCs presence accounted for an increased ratio of antibodies anti-SSA (OR = 3.13, 95% CI: 1.25-7.85, p = 0.02, I 2 = 79%), anti-SSB (OR = 3.94, 95% CI: 1.50-10.37, p = 0.0005, I 2 = 80%), and RFs presence (OR = 3.12, 95% CI: 1.94-5.00, p < 0.00001, I 2 = 0%)., Conclusions: This study showed that the association between ectopic GC in salivary glands identifies a clinical subset characterized by autoantibodies presence, and probably pSS patients affected from a more severe disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Berardicurti, Ruscitti, Di Benedetto, D’Andrea, Navarini, Marino, Cipriani and Giacomelli.)

Purpose: The prevalence of peripheral nervous system (PNS) involvement in primary Sjögren's syndrome (pSS) has been reported to range from 2% to over 50%. Bias in study designs, including low number of patients and unclearly defined rheumatological and neurological diagnosis could explain such variability. Consequently, the exact depiction of PNS involvement in pSS is still lacking. This study aimed at analyzing the prevalence and the clinical and laboratory factors associated with PNS involvement in a very large cohort of well-characterized pSS patients with a clearly defined neurological diagnosis., Methods: Clinical and serological data of 1,695 pSS patients with specific and accurate information on PNS involvement were analyzed. Comparisons between patients with and without PNS involvement and between patients with distinct subsets of PNS manifestations were performed., Results: Prevalence of PNS involvement was 3.7%. The most frequent types observed were pure sensory neuropathies and axonal sensorimotor polyneuropathies (SMP). Patients with PNS involvement exhibited a more active disease profile and were more frequently treated with immunosuppressants. Intriguingly, clinical and serological negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinemia, principally characterized patients with SMP, while subjects with pure sensory neuropathy displayed a milder phenotype., Conclusion: Our results highlight that PNS involvement is rather rare, but prognostically relevant in pSS. Main adverse prognostic features characterize patients with SMP, while pure sensory neuropathies are usually associated with a mild clinical picture. These findings, useful for patient stratification, may suggest protean pathogenic pathways underlying different types of PNS manifestations in pSS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cafaro, Perricone, Carubbi, Baldini, Quartuccio, Priori, Berardicurti, Ferro, Gandolfo, Gattamelata, Giacomelli, De Vita, Gerli and Bartoloni.)

Objectives: Interleukin (IL)-1β 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.

Rheumatoid arthritis (RA) is an inflammatory disease typically affecting the joints, but the systemic inflammatory process may involve other tissues and organs. Many extra-articular manifestations are recognized, which are related to worse long outcomes. Rheumatoid nodules are the most common extra-articular feature, found in about 30% of patients. Secondary Sjögren's syndrome and pulmonary manifestations are observed in almost 10% of patients, also in the early disease. Active RA with high disease activity has been associated with an increased risk of such features. Male gender, smoking habit, severe joint disease, worse function, high pro-inflammatory markers levels, high titer of rheumatoid factor, and HLA-related shared epitope have been reported as clinical predictors of occurrence of these rheumatoid complications. In addition, there is a little evidence deriving from randomized controlled trials in this field, thus the therapeutic strategy is mainly empiric and based on small case series and retrospective studies. However, considering that these extra-articular manifestations are usually related to the more active and severe RA, an aggressive therapeutic strategy is usually employed in view of the poor outcomes of these patients. The extra-articular features of RA remain, despite the improvement of joint damage, a major diagnostic and therapeutic challenge, since these are associated with a poor prognosis and need to be early recognized and promptly managed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients., (Copyright © 2020. Published by Elsevier B.V.)

Introduction : On June 2020, the first case of concurrent Covid-19 and Kawasaki disease (KD) was published. After this first description, further works reported new cases of children affected by KD and KD-like syndrome after SARS-CoV-2 infection. The clinical and biochemical features of these patients differed from the historical cohorts of KD, suggesting the possibility of a new multi-systemic inflammatory syndrome. Is still unclear if this new clinical entity, often referred as pediatric inflammatory multisystem syndrome (PIMS) or multi-system inflammatory syndrome in children (MIS-C), could be considered as part of the KD spectrum or is a new disease with different pathogenic mechanisms and uniquely linked to SARS-CoV-2 infection. The authors searched the available literature in MedLine (via Pubmed) with the terms ('coronaviruses' OR 'coronavirus') AND ('Kawasaki disease') for English studies without any temporal limit. Areas covered : This review aims to comprehensively describe multisystem inflammatory syndromes affecting children during Coronaviruses outbreak, and to evaluate the possible pathogenic role of human Coronaviridae in KD and KD-like syndromes. Expert opinion : An increased incidence of PIMS-TS, during the Covid-19 pandemic has been reported, suggesting that SARS-CoV-2 may trigger a severe hyper-inflammatory syndrome in childhood. The pathophysiological mechanisms of this disease are still unclear. Based on these findings, SARS-CoV-2 may be considered another trigger in the complex mosaic about the relationship among infectious agents and the occurrence of systemic hyper-inflammation related syndromes.

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.

Background: Different proportions of musculoskeletal or autoimmune manifestations associated with COVID-19 have been reported in literature. We performed a systematic review and meta-analysis with the aim of assessing the prevalence of rheumatic manifestations in patients affected by COVID-19, as initial symptom or during disease course., Methods: A database search was run on May 18th, 2020, using two distinct strategies. We were interested in the percentage of symptoms of potential rheumatologic interest observed in large population studies of COVID-19 cases, and in identifying uncommon autoimmune disorders described in patients with COVID-19. For manifestations individually reported, a meta-analysis was performed taking into consideration the proportion of COVID-19 patients presenting the symptom., Results: Eighty eight original articles were included in the systematic review and 51 in the meta-analysis. We found pooled estimates of 19% for muscle pain and 32% for fatigue as initial symptom of COVID-19 presentation and, respectively, of 16 and 36% during the disease course. Only one article discussed arthralgia as unique symptom. Additionally, we found that vasculitis, chilblains, presence of autoantibodies commonly found in patients with rheumatic diseases, or autoimmune haematological and neurological disorders have all been reported in patients with COVID-19., Conclusions: In conclusion, our review and meta-analysis emphasises that symptoms potentially leading to rheumatologic referral are common in patients with COVID-19. Therefore, COVID-19 is a new differential diagnosis to bear in mind when evaluating patients with musculoskeletal symptoms and rheumatologists might play a crucial role in identifying COVID-19 cases in early phases of the illness., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Ferritin is an iron-binding molecule, which comprises 24 subunits, heavy (FeH) and light (FeL) subunits, suggested to have a pathogenic role by the 'hyperferritinemic syndrome'. In this work, we tested (1) FeH and FeL in bone marrow (BM) and sera in patients with macrophage activation syndrome (MAS); (2) pro-inflammatory effects of ferritin, FeL, and FeH on macrophages; (3) ability of FeH-stimulated macrophages to stimulate the proliferation of peripheral blood mononuclear cells (PBMCs); (4) production of mature IL-1β and IL-12p70 in extracellular compartments of FeH-stimulated macrophages. Immunofluorescence analysis and liquid chromatography mass spectrometry (LC-MS/MS) based proteomics were performed to identify FeL and FeH in BM and sera, respectively, in the same patients. Macrophages were stimulated with ferritin, FeH, and FeL to assess pro-inflammatory effects by RT-PCR and western blot. The proliferation of co-cultured PBMCs with FeH-stimulated macrophages was tested. Immunofluorescence showed an increased FeH expression in BMs, whereas LC-MS/MS identified that FeL was mainly represented in sera. FeH induced a significant increase of gene expressions of IL-1β, IL-6, IL-12, and TNF-α, more marked with FeH, which also stimulated NLRP3. FeH-stimulated macrophages enhanced the proliferation of PBMCs. The ELISA assays showed that mature form of IL-1β and IL-12p70 were increased, in extracellular compartments of FeH-stimulated macrophages. Our results showed FeH in BM biopsies of MAS patients, whereas, LC-MS/MS identified FeL in the sera. FeH showed pro-inflammatory effects on macrophages, stimulated NLRP3, and increased PBMCs proliferation.

Background: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown aetiology usually affecting young adults. Interestingly, recent evidence from the juvenile counterpart of AOSD suggested the emergent high fatality rate of lung disease (LD) in these patients. In this work, we aimed to characterise LD in AOSD, to identify associated clinical features and predictive factors, and to describe long-term outcomes of the disease comparing patients with LD and those without., Methods: A retrospective assessment of prospectively followed patients, from January 2001 to December 2019, was provided to describe the rate of LD in AOSD, associated clinical features and predictive factors, and long-term outcomes. Patients with AOSD, who were included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort, were assessed., Results: Out of 147 patients included in GIRRCS cohort, 18 (12.25%) patients were reported to be affected by LD, at the time of diagnosis of AOSD, who were characterised by older age, a higher prevalence of myalgia, of lymph node involvement, of pleuritis, and abdominal pain. Furthermore, patients with LD showed higher values of systemic score and ferritin. Among those clinical variables, older age and systemic score were also independently predictors of LD. Chest CT scans were also obtained, and the most common finding was the peripheral consolidations in 8 (44.4%) patients. Finally, a higher mortality rate, of 38.9%, was registered in patients with LD than others, since it was associated with a significant decreased survival rate., Conclusions: The presence of LD could suggest an emergent cause of mortality in AOSD, as observed in juvenile counterpart recognising a further marker of severity and poor prognosis to be careful evaluated. Patients with LD were also characterised by some clinical features, higher values of systemic score and ferritin than the others, identifying a subset of patients mostly burdened by systemic signs and symptoms. Although specific designed future studies are needed to fully elucidate the significance of LD in AOSD, a more accurate evaluation and management of this feature could improve the long-term outcomes of these patients.

Introduction: Glucocorticoids (GCs) are key actors in RA management, despite the increasing number of available drugs. In fact, due to their efficacy and safety, the combination therapy between GCs and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) is still recommended in the early phase of RA treatment, because improving the long-term results., Areas Covered: In this paper, we reviewed the role of GCs in RA management, focusing on mechanisms of action as well as the benefit/risk ratio of GCs and newer therapeutic formulations. Furthermore, we analyzed GCs DMARDs proprieties on disease activity and their long-term effects on radiographic damage. We designed a narrative review aimed to provide an overview concerning GCs in RA management., Expert Opinion: A large amount of evidence supports the use of GCs in RA, especially in the earliest phases of the disease. Besides GCs symptomatic effects due to their strong anti-inflammatory effects, data from several randomized clinical trials have shown a substantial benefit of low-dose GCs in inhibiting the radiographic damage, thus highlighting GCs DMARDs properties. Besides their recognized role in the treatment of early RA, systematic monitoring of adverse events should be recommended to minimize GCs toxicity.