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Background:Chronic pain is one of the most critical symptoms reported by patients with Rheumatoid Arthritis, and even when joint inflammation improves, disabling residual pain may persist in a significant number of patients. During chronic inflammation, microglial cells, characterized by TMEM119 expression, acquire an activated phenotype characterized by the production of different pro-inflammatory cytokines and pain-related molecules, leading to a neuroinflammation process. Among these mediators, the brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is pivotal in generating abnormal pain perception, leading to nociplastic pain (1). IL-6, a Janus Kinase 1 (JAK1)-dependent pro-inflammatory cytokine, seems critical for the production of BDNF (2). Treatment with Upadacitinib, a JAK1 inhibitor, has been proven effective in improving disease activity and relieving pain quickly (3); nonetheless, the biological mechanisms underlying its efficacy in pain perception still need further investigation.Objectives:This study aims to investigate whether and how Upadacitinib may affect pain-related and neuroinflammation-related molecules expression in monocyte-derived microglia, specifically regarding BDNF.Methods:Microglia were differentiated from monocytes by treatment with NGF, MCP-1, IL-34, GM-CSF, and M-CSF for 14 days and further activated toward a pro-inflammatory phenotype using LPS and IFN-gamma, as summarized in Figure 1A. For all the experiments, microglia were exposed to six conditions in a culture medium for 48 hours: A1 untreated, A2 IL-6, A3 IL-6+Upadacitinib 0.1 uM, B1 IL-6+Upadacitinib 1 uM, B2 Upadacitinib 0.1 uM, and B3 Upadacitinib 1 uM. TMEM119 and BDNF expression in microglia was evaluated by immunofluorescence. Intracellular BDNF levels were analyzed by flow cytometry and Western Blot. In all the culture conditions, microglia underwent RNA-sequencing analysis. RNA from microglia was extracted using all prep DNA/RNA/miRNA universal kits (Qiagen, Germany), and bulk RNA sequencing was carried out using the Illumina system. Heatmaps were generated in RStudio statistical software (R version 3.3.0+; Boston, MA, USA) with the NMF package. All the other statistical analyses have been performed using GraphPad Prism v.10 (Boston, MA, USA).Results:TMEM199, a microglia marker, was expressed at baseline condition (Figure 1B) and BDNF (Figure 1C). Flow cytometry analysis showed that the treatment of Upadacitinib, both at the concentration of 0.1 uM and 1 uM, alone and in combination with IL-6, reduced BDNF levels in microglial cells compared to the untreated (A1) and IL-6 (A2) conditions (Figure 1D, * p<0.05). Western blot analysis confirmed that microglia treated with the combination of IL-6 and Upadacitinib (both 0.1 uM and 1 uM) showed a decreased production of BDNF compared to the microglia treated with IL-6 alone (p<0.0001). Transcriptomic analysis showed that Upadacitinib is able to reduce gene expression of JAK/STAT signaling (Figure 1E). Moreover, the neuroinflammation-related pathways are affected by Upadacitinib treatment toward a less pro-inflammatory phenotype (Figure 1F). Furthermore, Upadacitinib treatment, alone or in combination with IL-6, induces a modulation of acute and chronic pain-related genes.Conclusion:Our results show that Upadacitinib is crucial in modulating gene expression in microglia, characterized by decreased JAK/STAT, neuroinflammatory, acute, and chronic pain-related pathways. Moreover, in this cell type, Upadacitinib reduces the production of BDNF, a molecule involved in pain perception and nociplastic mechanisms.REFERENCES:[1] Atta AA et al, Inflammopharmacology 2023;31:1053-67[2] Schulte-Herbrüggen O et al, J Neuroimmunol 2005;160:204-9[3] Bergman M et al, Arthritis Res Ther 2022;24:155Acknowledgements:NIL.Disclosure of Interests:Luca Navarini Sanofi, GSK, AbbVie, Novartis, AbbVie, MSD, Italfarmaco, UCB, Novartis, Janssen-Cilag, GSK, Eli-Lilly, Sanofi, Marta Vomero: None declared, Erika Corberi: None declared, Onorina Berardicurti: None declared, Giulia Imperatori: None declared, Damiano Currado: None declared, Lyubomyra Kun: None declared, Francesca Trunfio: None declared, Francesca Saracino: None declared, Ludovica Lamberti: None declared, Annalisa Marino: None declared, Livia La Barbera: None declared, Paraskevi Krashia: None declared, Marcello D’Amelio: None declared, Roberto Giacomelli: None declared

Background:Hope is a goal-orientated cognitive construct comprising two components: pathways (achieving goals strategy) and agency (inspiring thoughts motivating to pursue goals). In rheumatic diseases, Hope is related to compliance and correlates with depression and symptoms worsening. Patients who experience chronic pain often tend to develop anxiety, depression, and a lack of hope regarding the improvement of their clinical condition. All of these can further increase the severity of the disease and resistance to various treatments.Objectives:The present study aims to assess Hope levels in patients with Fibromyalgia (FM) compared to healthy subjects (HS) and investigate whether a Mindfulness-based stress reduction (MBSR) intervention could increase Hope levels in FM patients and improve their physical and psychological status.Methods:64 FM female patients were consecutively enrolled in Campus Bio-Medico of Rome outpatient clinics and randomly assigned to either an MBSR intervention (n=31, consisting of 6 online sessions once a week) or not (n = 32). Moreover, 47 age- and sex-matched HS were recruited. All the groups completed the Adult Hope Scale (AHS) questionnaire at baseline. Only FM patients completed psychometric questionnaires at baseline and after three months: AHS, HADS to detect anxiety and depression symptoms, VAS-pain to assess pain, SCS to assess self-compassion, RS-14 to assess resilience, PCS to assess pain catastrophizing, SF-36 to assess health-related quality of life, PSS to assess stress, TAS-20 to assess alexithymia. FM disease severity has been evaluated by WPI, SSS, FSS, and FIQ-R. Continuous variables have been analyzed using the Mann-Whitney test for independent observations and the Wilcoxon test for paired data, while contingency tables have been analyzed using the Chi2 test. The statistical analysis has been performed using Stata v.14.Results:Comparative analysis at baseline showed that patients with FM have lower levels of hope as compared with HS [AHS 26 (24-27) and 22 (19-24), respectively, p<0.0001]. Both AHS Agency [13 (12-14) in FM group and 10 (9-12) in HS, p<0.0001] and AHS Pathways [13 (12-14) in FM group and 12 (10-13) in HS, p <0.0001] are reduced in FM patients compared to HS (Table 1). FM patients assigned to the MBSR group showed a significant improvement comparing baseline and after MBSR in WPI (p= 0.0300), SSS (p= 0.0141), FSS (p= 0.0104), FIQ-R (p <0.0001), HADS (p= 0.0005), PCS (p=0.0004), VAS-pain (p=0.0006) and PSS (p=0.0431). However, comparing baseline and after MBSR FM patients did not show improvement in SCS (p= 0.0888) [although statistically significant results were achieved in the SCS self-judgement (p= 0.0345) and SCS Isolation (p= 0.0078) subdomains], TAS-20 (p= 0.4535), RS-14 (p=0.0885) and SF-36 (p= 0.0545) [although significant variations were observed in the SF-36 Physical Functioning (p=0.0493), SF-36 Role-physical (p= 0.0028), SF-36 Social Functioning (p= 0.0003), and SF-36 Bodily Pain (p= 0.0001)] (Table 2). FM patients not undergoing MBSR intervention did not improve comparing baseline and after MBSR in any questionnaire.Conclusion:Hope levels in FM patients are significantly reduced compared to the healthy population. In FM, MBSR intervention induces improvement in the levels of Hope and, more specifically, its Agency component. This increase is associated with simultaneous improvement in physical function and various psychometric variables. Indeed, there is a reduction in anxiety, depression, perceived stress, and VAS-pain, as well as an improvement in FIQ-R and FSS, scores commonly used in clinical practice to assess the severity and impact of the disease on daily life. Therefore, MBSR is a promising treatment method for Fibromyalgia Syndrome. This chronic and debilitating condition still requires studies to investigate various aspects of the disease, including the identification of specific and effective therapies to improve patients’ quality of life.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:In rheumatic diseases, increasing emphasis is put on the role of psychosocial factors in the experience of pain. Among these factors, pain catastrophizing (PC), an inclination to exaggerate in describing pain, to ruminate, or to feel helplessness about it, has emerged. While associated with subjective perception, PC doesn’t align with inflammation biomarkers. The mechanisms underlying these effects remain not fully elucidated, positioning PC as a key variable that might shed light on why certain patients struggle to achieve treatment targets. Many studies demonstrate impact of Rheumatoid Arthritis (RA) on physical, psychological, and social aspects, impairing quality of life. In RA patients, PC is more prevalent than in the general population, impacting drug retention.Objectives:We aimed to evaluate PC and its related domains (Rumination, Magnification, and Helplessness) in RA patients and assess its impact on disease activity in models adjusted for different psychometric domains, such as anxious and depressive symptoms.Methods:We conducted a multi-center, cross-sectional, observational study on consecutive RA patients fulfilling ACR/EULAR criteria. Comorbidities and antibody status were collected at enrolment. Disease activity has been assessed with composite indices, such as Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI). For assessment of physical, psychological, and social status validated questionnaires have been administered: Health Assessment Questionnaire, Hospital Anxiety and Depression Scale, Trait Hope Scale and its domain Agency and Pathway, Acceptance and Action Questionnaire and Compassionate Engagement and Action Scales. Furthermore, PC has been assessed using the Pain Catastrophising Scale (PCS), characterized by 3 domains: rumination, magnification and helplessness. Univariate and multivariable regressions were performed to evaluate possible predictors of disease activity, including PC and its domains. All the statistical analysis has been performed using Stata v. 14 (College Station, Texas, USA)Results:We enrolled 158 RA patients (age 61 (51-69) years, males/females 29.11/70.9%). In this subset, we observed that the median CDAI value was 8.05 (2-14.5) and SDAI 8.14 (2.26-14.7). Concomitant fibromyalgia was present in 17.97% and lung involvement (LI) in 6.8% of participants. The analysis of the PCS showed a median value of 17 (8-26) and its specific domains showed helplessness 6 (2-11), Rumination 7 (3-11), Magnification 2 (1-4). The main demographic, anthropometric, and clinical characteristics of the study population are reported in Table 1. Using the cut-off point marking the difference of clinically significant from non-significant PC (PCS=30), patients with PCS >30 showed a positive association with the values of tender joints (p=0.0007), swollen joints (p=0.0336), VAS pain (p=0.0086), patients’ global assessment (p=0.0002), physician global assessment (p=0.0129), CDAI (p<0.0001), SDAI (p=0.0001) and LI (p=0.013). Univariable and multivariable regression considering SDAI as a dependent variable are summarized in Table 2. In multivariable analysis, PCS is independently associated with SDAI (coeff 0.22467, 95%CI 0.923 to 0.357, p=0.001), whilst anxious and depressive symptoms are not. The same results were reported for the PCS domains helplessness (coeff 0.5947942, 95%CI 0.3032154 to 0.8863731, p<0.0001) and rumination (coeff 0.4921229, 95%CI 0.2190804 to 0.7651653, p=0.001) but not for magnification (p=0.4).Conclusion:In our study, we found that PC, a maladaptive cognitive perception of pain, negatively impacts disease activity, thus limiting the achievement of therapeutic targets. We established a significant association between PCS (total PCS and domains: rumination, magnification, helplessness) and SDAI levels, confirming PC’s interference with achieving low disease activity and remission. Notably, PC is associated with SDAI independently from anxious and depressive symptoms, the latter previously associated with disease activity. Thus, PC might mediate the relationship between depressive symptoms and RA disease activity.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Psoriatic Arthritis (PSA) is one of the most common inflammatory arthritis. PSA induces joint pain and inflammation, as well as a reduction in quality of life and workability. According to EULAR recommendations, regular physical activity is strongly recommended in patients with inflammatory arthritis, to maintain adequate joint movement and reduce cardiovascular risk, which is increased in PsA. However, the presence of pain and joint deformities could limit the ability of PsA patients to exercise. Furthermore, psychosocial factors are important determinants of pain experience in patients with inflammatory arthritis. The Fear Avoidance Model is used widely to explain how psychological factors affect the experience of pain and the development of chronic pain and disability, suggesting that patients with fear avoidance beliefs are less likely to confront pain-related problems and are less active in the coping process.Many questionnaires have been developed to identify fear avoidance beliefs. Among them, the Fear-Avoidance Beliefs Questionnaire (FABQ) is a 16-item questionnaire that assesses a person’s fear-avoidance beliefs about physical activity and work.Objectives:Our study aimed to evaluate the prevalence of physical activity avoidance in patients with PsA. Moreover, we assessed the demographic, PsA-related, and psychometric variables independently associated with physical activity avoidance.Methods:A single-center, cross-sectional, observational study has been carried out on consecutive PsA patients, fulfilling CASPAR criteria. Physical activity avoidance and associated potential psychological domains have been assessed with validated questionnaires. In particular, FABQ (Fear Avoidance Beliefs Questionnaire) has been used to assess how a patient’s fear of pain may contribute to avoiding physical activity. Additionally, uni- and multivariate linear regressions have been performed to evaluate demographic, pathology-related, or psychometric factors potentially related to physical activity avoidance. All the statistical analysis has been performed using Stata v.14 (College Station, Texas, USA).Results:The main demographic, anthropometric, and clinical characteristics of the study population are reported in Table 1. Particularly, patients showed age 56 (33-74) years, males/females ratio 30.8%/69.2%, Disease Activity in PsA (DAPSA) 14.3 (1.5-29.7), BASDAI 5.45 (1.1-8.72). PsA patients with FABQ PA≥ 15 (cut-off point marking high levels of fear-avoidance beliefs related to physical activity) represent 27.69 % of the population. Concomitant fibromyalgia was present in 37.1% of the participants. We observed that the proportion of patients with fibromyalgia among those with FABQ PA≥ 15 was 52.9 %.PCS (Pain Catastrophising Scale) median value was 20.97 (1-40), SF36 PCS (Physical Component Score) median value was 35.3 (21.5-56.6) and FABQ PA median value was 11.4 (1-23).Moreover, patients with FABQ ≥15 showed a higher BASDAI, PCS, and SF36 PCS than patients with FABQ PA <15 (p-values 0.0002, 0.030, and 0.002, respectively).As reported in Table 2, in multivariable linear regression, independent predictors of physical activity avoidance were the SF36-PCS and anxiety symptoms assessed by HADS. No disease activity index was independently associated with FABQ.Conclusion:This study suggests that avoiding physical activity in PsA patients may depend on physical functioning and anxiety symptoms rather than disease activity.TJ: Tender Joints; SJ: Swollen Joints; PP: Patient Pain, PtGA: Patient Global Assessment; CRP: c-reactive protein; PASI: Psoriasis Area Severity Index; DAPSA: Disease Activity in PSoriatic Arthritis; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; mFABQ: modified Fear-Avoidance Belief Questionnaire; FABQ PA: FABQ Physical Activity; HAQ: Health Assessment Questionnaire; HADS: Hospital Anxiety and Depression Scale; PCS: Pain Catastrophising Scale; IPAQ: International Physical Activity Questionnaire; SF36 PCS: Short Form Health Survey 36, Physical Component Summary; SF36 MCS: SF36, Mental Component SummaryREFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Chronic pain and inflammation are common features of rheumatic conditions such as Psoriatic Arthritis (PsA) and Axial Spondyloarthritis (axSpA), often necessitating prolonged medication use for effective management. Maintaining drug retention is essential for achieving disease control and improving patients’ quality of life. In recent years, several studies have turned their attention to real-world scenarios, examining the extended-term usage of biologic disease-modifying antirheumatic drugs (bDMARDs) in spondyloarthritis; furthermore, the factors linked to the retention rate of bDMARDs in remain a pivotal question to be addressed.Objectives: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. To assess the drug discontinuation rate, any occurrence of withdrawal therapy and adverse events recognized or suspected as linked to therapies were recorded. Pain Catastrophizing, including its domains of Helplessness, Rumination, and Magnification, was assessed using the Pain Catastrophizing Scale (PCS). Univariable and multivariable regression analyses were utilized to identify factors associated with drug retention.Results:In the PsA group, patients who discontinued therapy early had higher baseline disease activity and a higher incidence of comorbid fibromyalgia. Notably, pain catastrophizing, specifically the domains of Helplessness, Magnification, and Rumination, were significantly elevated in PsA patients who interrupted their treatment. The univariable linear regression (Table 1) confirmed fibromyalgia comorbidity, corticosteroids assumption, Disease Activity for Psoriatic Arthritis (DAPSA) at baseline and PC levels as predictors for drug suspension within two years follow-up. Of note, the multivariable logistic regression (model adjusted for age, sex, DAPSA and corticosteroids use) showed significant relationship between PsA participants drug discontinuation and PCS (OR 1.04, 95% CI 1.004- 1.074, p=0.02), helplessness (OR 1.09, 95% CI 1.01-1.18, p=0.03), rumination (OR 1.10, 95% CI 1.01- 1.20), but not for magnification domain (OR1.15, 95% CI 0.97-1.36, p=0.09). In axSpA, drug discontinuation was more frequent among females, those with shorter disease duration, higher baseline disease activity, and elevated levels of pain catastrophizing. Of note, the univariable logistic regression (Table 2) established female gender, baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), PCS and all its components helplessness, magnification, and rumination as disease predictor of treatment suspension before two years follow-up. However, limited events in axSpA patients precluded a multivariate analysis.Conclusion:Pain catastrophizing has emerged as a significant factor affecting drug retention in PsA and axSpA patients. The findings from the study discussed here shed light on the importance of assessing and addressing pain catastrophizing in clinical practice. By recognizing and intervening in the psychological aspects of pain, healthcare providers can contribute to better outcomes for patients with PsA and axSpA, ultimately improving their quality of life and overall well-being.Table 1.Two-year discontinuation (PsA participants)UnivariableIndependent variablesOR95%CIpFibromyalgia3.221.42-7.280.005CCS2.351.02-5.400.04TJ1.101.02-1.180.01PP1.091.00- 1.180.04PtGa1.31.12 1.49<0.0001DAPSA1.061.02 1.100.001PCS1.051.02 1.08<0.0001Helplessness1.121.05 1.190.001Rumination1.131.05 1.21<0.001Magnification1.221.05 1.420.009Table 2.Two-year discontinuation (AxSpA participants)UnivariableIndependent variablesOR95%CIpSex3.681.01 13.400.04BASDAI1.811.281398 2.5723260.001Asdas pcr2.491.304764 4.7234660.006PCS1.131.05533 1.202472<0.0001Helplessness1.241.092015 1.4093920.001Rumination1.251.07672 1.4577350.004Magnification1.351.024664 1.7890550.03REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Comparative analytical assessment (CAA) between the reference product and the proposed product forms the basis of the biosimilarity demonstration. Though Dynamic Light Scattering (DLS) has been implemented for CAA, its capability beyond signature peak for similarity assessments has remained unexplored. Herein, we have developed a innovative forced degradation based sweet spot method consisting of signature peak, temperature range, increment and hold time using high throughput-DLS (HT-DLS) to show similarity in hydrodynamic size between products. In our study, we used rituximab, its biosimilars, and insulin analogs as model products to demonstrate product similarity in hydrodynamic size (D h ) size through the HT-DLS sweet spot approach. Our data indicate that temperature range, temperature increment, hold time, and regularization algorithm, all play a role in showing analytical similarity in D h size. Our data also indicate that establishing DLS signature peaks of the products is insufficient to show analytical similarity in D h size distribution. Additionally, the temperature range (sweet spot) varies from product to product. Principal component analysis modeling was used for detailed data interpretation. Overall, our HT-DLS based sweet spot method provided informative data to support similarity in D h size distribution.

Oral mucositis (OM) is a common side effect experienced during haematopoietic SCT (HSCT), and it can have a significant impact on the quality of life of patients. A descriptive nurse-led study was undertaken in 19-member centres of the Italian national transplant group (GITMO) evaluating incidence, severity and duration of OM in patients undergoing HSCT. Data from 1841 patients between 2002 and 2006 was analyzed. Initial medical history and oral cavity assessment was performed. Assessment was repeated on the day of transplant, then daily, using the WHO (World Health Organisation) oral toxicity scale. A total of 71% of the patients evaluated developed mucositis and 21.6% developed severe mucositis. Duration of OM in most cases lasted for 10–14 days and resolved along with marrow reconstitution. Oral mucostitis is a frequent side effect in patients undergoing HSCT. The onset of severe mucositis seems to be related to the conditioning regimen used. This database provides a descriptive overview of the incidence and severity of mucositis and has encouraged participating centres to adopt routine evaluation and measurement of the oral cavity. The assessment tools are still used in some centres, providing a basis for further collaborative research projects.

Cerebrospinal fluid (CSF)/plasma HIV-RNA ratio has been associated with residual neurocognitive impairment on cART, leading us to hypothesize a specific peripheral and/or CSF immune feature in patients with high CSF/plasma ratio (≥ 1). In patients with diverse pre-cART CSF/plasma ratio (61/70 with CSF/plasma ratio < 1, L-CSF, 9/70 with CSF/plasma ratio ≥ 1, H-CSF), we investigated the effects of 12 months of effective cART on peripheral and CSF inflammatory markers, on T cell activation/maturation and HIV/CMV-specific intracellular cytokine pattern. We also studied the possible clinical association between peripheral/CSF pro-inflammatory milieu and neurocognitive screening tests (MMSE, FAB, IHDS). Prior to cART, the two groups were comparable for peripheral and CSF inflammation, T cell activation/proliferation and maturation, and HIV/CMV-specific response. Upon cART initiation, both H-CSF and L-CSF featured a significant reduction in plasma TNF-α and circulating CD8 activation, with a redistribution of memory/naïve T cell subsets in L-CSF alone. In the CSF compartment, cART seemed able to reduce pro-inflammatory cytokine/chemokine levels in both H-CSF and L-CSF patients. Interestingly, despite a reduction in the pro-inflammatory milieu , no changes were shown in neurocognitive screening tests in both patients’ groups. We hereby show that 12-month cART is able to reduce intratechal and peripheral pro-inflammatory burden; a longer cART exposure and a more comprehensive neuropsychological evaluation might be necessary to gain a broader insight into the possible effects on neurocognitive performance.

We present a decision suppport tool for the comparison and selection of projects of integrated renovation of derelict buildings and areas for the purpose of urban regeneration. Each project is defined as a subset of derelict properties to renovate together with their respective designated use, and is scored by the decision support tool on two criteria: expected effort and estimated effectiveness in terms of improved urban capabilities in the urban area of interest. The expected effort is estimated as a global transformation cost, factoring in legal and management overhead costs as well as possible economies of scale. The effectiveness in evaluated in terms of extension of urban capabilities centred on walkable distances. We have implemented a bi-objective evolutionary search algorithm to address the computational complexity of the problem of search for efficient (non-dominated) projects over the two criteria. For the purpose of illustration, we present an example case-study application on the historical core of the city of Sassari, Italy.