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Introduction/Objective: The efficacy of biologic therapy in the treatment of rheumatoid arthritis (RA) has been well-established but, in practice, a quarter of patients will either not respond to the first biologic agent or will suffer an adverse event requiring a switch to a different drug. While clinical guidelines exist to help guide therapy and previous studies have examined sequential use of anti-TNF agents, there is little data to inform a multiple switch strategy. Our aim was to measure the efficacy of multiple switches of biologic in severe refractory RA. Methods: We enrolled 111 patients whose therapy with one anti-TNF agent had failed in this open-label observational study. These patients were all treated with a second biologic agent and 27 ultimately required treatment with a third. The response to the therapy and disease activity were assessed at 6 and 12 months after each switch. Results: The remission rates at 6 months were lower than previously reported and the initiation of a second biologic agent resulted in significant improvement at 12 months, including DAS remission in 36% of patients. The response in those receiving a third biologic was less pronounced, as might be expected in this relatively treatment-refractory population. In this group, only patients treated with tocilizumab had maintained remission at one year. Conclusion: Patients who do not respond to an anti-TNF agent often benefit from being switched to a second, or even third, biologic. Importantly, it may take longer than expected to fully assess the effectiveness of a second or third agent in patients with refractory disease.

Physical activity (PA) has a fundamental role in subjects with rheumatoid arthritis (RA), in terms of motility, joint function, muscle wasting, BMI (body mass index), cardiovascular fitness (CRF), mental health, but also changes in bioactive molecules that might influence the disease activity and patient’s wellbeing. A systematic search of Pubmed and Google Scholar library was performed for clinical trials, randomized-controlled trials, and pilot studies published in the last 15 years. Studies using as adjunctive therapy aerobic exercise, high-intensity interval training (HIIT), and moderate training as yoga were included. The available papers shown that exercise programs improve joint’s mobility and flexibility and the overall health status, without differences regarding age, gender or disease activity. All these findings are supported by the modulatory role of exercise-induced cytokines as interleukin-6 (IL-6) and irisin, together with a reduction of inflammatory markers.

Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS). Our aim was to evaluate serum anti-vinculin antibodies in patients with SSc. Patients were recruited from two SSc centers: group I (GI-enriched group), University of Leeds, UK, and Group II (vascular predominant), University of California, Los Angeles. Serum samples of patients recruited from two SSc centres, Group I ( GI enriched group), University of Leeds, UK and Group II (Vascular predominant), University of California, Los Angeles) were collected. Samples from age- and sex-matched healthy volunteers (N = 88) were used as controls. Group I (GI-enriched group, N = 83) patients were 58 [50–67] years old; 83% were females with a median body mass index (BMI) of 20.3 (21.2 ± 4.5) [18–23]. Group II (vascular-enriched group, N = 72) patients were 58 [50–67] years old; 80% were female, and BMI was 23.9 (21.3–26.9). More subjects in group I had prominent GI involvement (N = 55, 66%) than group II (12, 16%), p ˂ 0.0001. Anti-vinculin antibody levels in SSc group I (1.3 [0.9]) were significantly higher than in HC (0.7 [0.8]; p = 0.002). When pooled, circulating anti-vinculin levels in both SSc groups remained significantly higher than in the HC group (p = 0.02). Higher anti-vinculin levels were associated with higher GI-visual analogue scale (GI-VAS) scores and specifically with GI-VAS scores of ≥ 4 (p < 0.0001). This study demonstrates that elevated anti-vinculin antibody levels are common in SSc and suggests a potential link between increased anti-vinculin levels and GI tract symptoms.

ObjectiveThere is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.MethodsA multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.ResultsThe overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.ConclusionOur study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

To realize a machine learning (ML) model to estimate the dose of low molecular weight heparin to be administered, preventing thromboembolism events in COVID-19 patients with active cancer. Methods: We used a dataset comprising 131 patients with active cancer and COVID-19. We considered five ML models: logistic regression, decision tree, random forest, support vector machine and Gaussian naive Bayes. We decided to implement the logistic regression model for our study. A model with 19 variables was analyzed. Data were randomly split into training (70%) and testing (30%) sets. Model performance was assessed by confusion matrix metrics on the testing data for each model as positive predictive value, sensitivity and F1-score. Results: We showed that the five selected models outperformed classical statistical methods of predictive validity and logistic regression was the most effective, being able to classify with an accuracy of 81%. The most relevant result was finding a patient-proof where python function was able to obtain the exact dose of low weight molecular heparin to be administered and thereby to prevent the occurrence of VTE. Conclusions: The world of machine learning and artificial intelligence is constantly developing. The identification of a specific LMWH dose for preventing VTE in very high-risk populations, such as the COVID-19 and active cancer population, might improve with the use of new training ML-based algorithms. Larger studies are needed to confirm our exploratory results.

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) represents a public health problem worldwide. COVID-19 triggers a maladaptive cytokine release commonly referred to as cytokine storm syndrome with increased production of proinflammatory cytokines, which also appears to contribute to chronic neuroinflammation and neurodegenerative disorders’ appearance, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, SARS-CoV-2 might enter the central nervous system through binding with the angiotensin converting enzyme 2 receptors which are highly expressed in glial cells and neurons. For this reason, an association between COVID-19, its dependent cytokine storm, and the development and/or progression of neurodegenerative disorders might be evaluated. Therefore, the aim of this review was to assess the impact of COVID-19 on neurodegenerative disorders, focusing on the possible increased mortality risk and/or deterioration of the clinical course of pre-existing chronic neurological diseases in patients with dementia.

Anemia occurs in 25 to 40% of SSc and predicts both mortality and PAH. There are numerous forms of anemia found in systemic sclerosis (SSc) including iron deficiency anemia (16 to 18%) often with gastric arteriovenous ectasia(GAVE), vitamin B12 and folate deficiency anemia and autoimmune anemia with hemolysis and reticulocytosis.

Malnutrition is a medical condition characterized by an unbalance between energy expenditure and nutritional intake. Intuitively, weight loss is the clinical manifestation that best represents malnutrition despite weight loss per se is not a synonym of malnutrition. The common definition of malnutrition is based on a body mass index (BMI, kg/m2) ≤18.5. Recently, the European Society of Clinical Nutrition and Metabolism (ESPEN) extended this definition to include the possibility to track changes in BMI based on weight loss in a specific amount of time resulting in the following combination: Weight loss (unintentional) > 10% indefinite of time, or >5% over the last 3 months combined with either BMI 70 years of age or fat free mass index (FFMI)

Percutaneous coronary intervention (PCI) is one of the most common procedures performed in medicine. However, its net benefit among patients with chronic kidney disease (CKD) is less well established than in the general population. The prevalence of patients suffering from both CAD and CKD is high, and is likely to increase in the coming years. Planning the adequate management of this group of patients is crucial to improve their outcome after PCI. This starts with proper preparation before the procedure, the use of all available means to reduce contrast during the procedure, and the implementation of modern strategies such as radial access and drug-eluting stents. At the end of the procedure, personalized antithrombotic therapy for the patient’s specific characteristics is advisable to account for the elevated ischemic and bleeding risk of these patients.

Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS). Our aim was to evaluate serum anti-vinculin antibodies in patients with SSc.Patients were recruited from two SSc centers: group I (GI-enriched group), University of Leeds, UK, and Group II (vascular predominant), University of California, Los Angeles. Serum samples of patients recruited from two SSc centres, Group I ( GI enriched group), University of Leeds, UK and Group II (Vascular predominant), University of California, Los Angeles) were collected. Samples from age- and sex-matched healthy volunteers (N = 88) were used as controls.Group I (GI-enriched group, N = 83) patients were 58 [50-67] years old; 83% were females with a median body mass index (BMI) of 20.3 (21.2 ± 4.5) [18-23]. Group II (vascular-enriched group, N = 72) patients were 58 [50-67] years old; 80% were female, and BMI was 23.9 (21.3-26.9). More subjects in group I had prominent GI involvement (N = 55, 66%) than group II (12, 16%), p ˂ 0.0001. Anti-vinculin antibody levels in SSc group I (1.3 [0.9]) were significantly higher than in HC (0.7 [0.8]; p = 0.002). When pooled, circulating anti-vinculin levels in both SSc groups remained significantly higher than in the HC group (p = 0.02). Higher anti-vinculin levels were associated with higher GI-visual analogue scale (GI-VAS) scores and specifically with GI-VAS scores of ≥ 4 (p0.0001).This study demonstrates that elevated anti-vinculin antibody levels are common in SSc and suggests a potential link between increased anti-vinculin levels and GI tract symptoms.• Anti-vinculin antibodies are elevated in systemic sclerosis and are relatively common. • In these SSc patients, anti-vinculin antibodies are associated with higher levels of GI symptoms in SSc. • A potential link between anti-vinculin antibodies and vascular system involvement was shown.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell–integrin interaction are sufficient to initiate profibrotic processes. SSc fibroblasts express both αvβ3 and αvβ5 integrins and their activation induces myofibroblasts differentiation. The aim of the present study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis. SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: HOCl alone (n=8), HOCl + Cilengitide (n=8), or Vehicle alone (n=8). Treatment with cilengitide 20 (mg/kg/i.p./day) was started 4 weeks after the first administration of HOCl and maintained throughout the remaining experimental period (2 weeks). Lung, skin, and heart fibrosis were evaluated by histology while kidney morphology by PAS staining. Collagen type I, focal adhesion kinase (FAK), and a-SMA were evaluated by immunostaining and p-FAK and TGF-β1 by Western blot and gene expression. Both cutaneous and pulmonary fibrosis induced by HOCl were attenuated by cilengitide treatment. Cilengitide administration reduced a-SMA, TGF-β1, and p-FAK expression and the increased deposition of fibrillar collagen in the heart and prevented glomeruli collapse in the kidneys. The inhibition of aνβ3 and aνβ5 integrin signaling prevented systemic fibrosis and renal vascular abnormalities in the reactive oxygen species model of SSc. Integrins aνβ3 and aνβ5 could prove useful as a therapeutic target in SSc.

Resume Objectifs L’objectif de la presente etude a ete d’evaluer la prevalence des atteintes de l’articulation temporomandibulaire (ATM) de la presentation clinique et des donnees de l’imagerie par resonance magnetique (IRM) dans une cohorte de patients du sud de l’Italie atteints de sclerodermie systemique (ScS). Methodes Vingt-sept patients atteints de ScS (12 ScS diffuse, 15 ScS limitee, âge moyen 53,9, ET ± 1,2) et 28 sujets sains (âge moyen 54,8, ET ± 4,2) ont ete inclus dans cette etude de cohorte observationnelle. Chez tous les patients on a realise un examen clinique visant a evaluer la presence de bruits de l’ATM, la douleur dans la region de l’ATM, la sensibilite des muscles masticateurs et la limitation de l’ouverture de la bouche ainsi qu’une evaluation de la douleur, un examen IRM et une evaluation des indices d’anamnese et de dysfonction. Resultats Dans le groupe de patients, les observations cliniques et par IRM ont revele un plus grand nombre de symptomes de l’ATM et de dysfonctions que dans le groupe temoin. Les distributions de frequence des symptomes ont ete significativement differentes (p Conclusion Cette etude montre que l’atteinte de l’ATM est courante chez les patients souffrant de ScS et est correlee avec la duree et la gravite de la maladie. Elle plaide pour la promotion d’un examen de l’ATM dans les services de rhumatologie, ainsi que d’une prise en charge de la douleur et de la fonction appropriee pour les patients.

Objectives: The aim of the present study was to assess the prevalence of temporomandibular joint (TMJ)symptoms, clinical and magnetic resonance imaging (MRI) findings in a cohort of Southern Italian patientswith SSc.Methods: Twenty-seven patients with SSc (12 diffuse, 15 limited, mean age 53.9, SD ± 1.2) and 28 healthysubjects (mean age 54.8, SD ± 4.2) were enrolled in this observational cohort study. In all patients, clinicalexamination for assessing the presence of TMJ sounds, pain in the TMJ area, tenderness of masticatorymuscles, limited mouth opening, pain assessment, MRI scan and Anamnestic and Dysfunctional Indexwere performed.Results: The test groups reported more clinical and MRI findings of TMJ symptoms and dysfunction thancontrol group. The frequency distributions of symptoms were significantly different (P < 0.05), in thetest groups for TMJ sounds, pain during mandibular movement and difficulty in the maximum mouthopening. There was also a significant decrease (P < 0.001), in the test groups, in the mean of leftward,rightward laterotrusion and protrusion. Correlation analysis allowed to affirm that maximum openingleftward laterotrusion, protrusion and click were significantly correlated to Modified Rodnan Skin Score.The mean duration of disease was significantly correlated, ever in total SSc group, only for the maximummouth opening value.Conclusion: This study demonstrates that TMJ involvement is common in SSc patients and is correlatedwith a length and involvement of disease and supports the notion that TMJ examination should be encour-aged in the rheumatology setting and clinicians should provide a right pain management and patientsupport. Objectives: The aim of the present study was to assess the prevalence of temporomandibular joint (TMJ)symptoms, clinical and magnetic resonance imaging (MRI) findings in a cohort of Southern Italian patientswith SSc.Methods: Twenty-seven patients with SSc (12 diffuse, 15 limited, mean age 53.9, SD ± 1.2) and 28 healthysubjects (mean age 54.8, SD ± 4.2) were enrolled in this observational cohort study. In all patients, clinicalexamination for assessing the presence of TMJ sounds, pain in the TMJ area, tenderness of masticatorymuscles, limited mouth opening, pain assessment, MRI scan and Anamnestic and Dysfunctional Indexwere performed.Results: The test groups reported more clinical and MRI findings of TMJ symptoms and dysfunction thancontrol group. The frequency distributions of symptoms were significantly different (P < 0.05), in thetest groups for TMJ sounds, pain during mandibular movement and difficulty in the maximum mouthopening. There was also a significant decrease (P < 0.001), in the test groups, in the mean of leftward,rightward laterotrusion and protrusion. Correlation analysis allowed to affirm that maximum openingleftward laterotrusion, protrusion and click were significantly correlated to Modified Rodnan Skin Score.The mean duration of disease was significantly correlated, ever in total SSc group, only for the maximummouth opening value.Conclusion: This study demonstrates that TMJ involvement is common in SSc patients and is correlatedwith a length and involvement of disease and supports the notion that TMJ examination should be encour-aged in the rheumatology setting and clinicians should provide a right pain management and patientsupport.

The demand for sensors capable of measuring low-abundant collagen in human fluids has highly increased in recent years. Indeed, collagen is expected to be a biomarker for chronic diseases and could monitor their progression. Here we show detection of highly diluted samples of collagen at picogram level thanks to an innovative pyro-electrohydrodynamic jet (p-jet) system. Through the intense electric fields generated by the pyroelectric eect in a ferroelectric crystal, the collagen solution was concentrated on a small area of a slide that was appropriately functionalized to bind proteins. The collagen molecules were labeled by an appropriate fluorophore to show how the number of tiny droplets influences the limit of detection of the technique. The results show that the p-jet is extremely promising for overcoming the current detection limits of collagen-based products in human fluids, performing 10 times better than the enzyme-linked immunosorbent assay (ELISA) and thus paving the way for the early diagnosis of related chronic diseases.

Background Macrovascular involvement in Systemic Sclerosis (SSc) is caused by proliferation of vascular smooth muscle cells within the intima of arteries (neointimal proliferation). The resulting decrease in arterial volume is responsible for the severity of Raynaud’s and for the onset of severe clinical manifestations such as Renal Crisis and Pulmonary Artery Hypertension. Several RCTs have demonstrated the efficacy of Endothelin Receptor Antagonists (ERAs) in targeting neointimal proliferation, which makes them to date, the only disease modifying agent available in SSc. Nevertheless, the lack of validated early diagnostics means the intention to treat with ERAs remains limited to the diagnosis of end stage clinical manifestations of neointimal proliferation, such as presence of Digital Ulcer (DU) and PAH. Objectives Here we aimed to determine the proof of concept validity of automated Digital Artery Volume Index (DAVIX) measured by non-contrast Time of Flight (TOF) MRI as an objective diagnostic tool to be used as surrogate outcome measure of neointimal proliferation in SSc. Methods 10 Healthy Volunteers (HV) and 8 SSc patients were enrolled. Six patients underwent longitudinal assessments at least 12 months apart. MRI scans were performed on a 3T Magnetom Verio (Siemens) and consisted of a VIBE 3D T1 scan and a 2D TOF sequence of 8 min. DAVIX was calculated as the percentage of the ratio of digital artery and the respective finger volumes. The vessels and fingers were manually outlined by an expert radiologist and used as a ‘gold standard’ (DAVIX-1) and compared to a 2nd independent radiologist assessment (DAVIX-2). An automated segmentation algorithm was developed using threshold based segmentation and region growing (DAVIX-A) and validated against gold standard. Intraclass correlation coefficient (ICC) and absolute agreement were calculated to estimate reliability. Bland-Altman bias and 95% limits of agreement (LoA) were calculated as well. Results SSc patients and HV had comparable age (44±8 vs 45±8) and gender (F:M=5:2 vs 4:2). 4 fingers were affected by DUs at baseline and two fingers were affected by new DU at follow up. Mean(±SD) DAVIX in HV was 1.21 (±0.39) with no significant difference among individual fingers. Mean DAVIX in SSc patients was 0.37 (±0.18) and 0.32 (±0.39) at baseline and follow-up, respectively (p Conclusions This proof of concept study demonstrated validity and sensitivity to change of DAVIX for the automated volumetric assessment of digital arteries, which reflected clinical worsening in patients with new DU. Larger, longitudinal studies are planned to assess DAVIX’ predictive value for the onset of DU and its potential use as early diagnostic of neointimal proliferation in SSc. Disclosure of Interest None declared

Background Malnutrition and severe gastrointestinal dysfunction are the cause of mortality in 4%–15% of systemic sclerosis (SSc) patients whereas overall gastrointestinal involvement is observed in 75%–90% of cases.1 Hence, a reliable tool for stratification of risk for malnutrition would be of great value in the clinical management of SSc. Objectives Here we set out to identify a combined index predictive of significant weight loss at 12 months employing Malnutrition Universal Screening Tool (MUST) and serum adiponectin to leptin ratio (A/L) already used in other conditions. Methods This was an international, multicentre, longitudinal study employing 180 SSc patients in two independent cohorts: a study cohort (110 consecutive SSc patients) enrolled from University of Messina (60) and University of Padova,50 and a validation cohort (70) at the University of Leeds. Serum A/L ratio was measured by ELISA. MUST score, which includes BMI and weight loss reported by the patient in the last 3–6 months, was calculated as described: 0=no, 1=mild,>2= moderate/severe risk of malnutrition. End point of the study was weight loss >10% of baseline weight at 12 months. Results The two cohorts showed no significant differences in demographic and clinical features. Overall, median BMI decreased over time in both study and validation cohorts (23.5 vs 22.35 and 23.44 vs 22.49, respectively; p 10% wt despite having “no” or “mild” MUST scores. Logistic regression analysis identified the combination of BMI and A/L as the best PREdictor of MAlnutrition in Systemic Sclerosis (PREMASS). The formula 12.18-(0.63*BMI)+(1.51*A/L) predicted the end point with AUC=0.91 (95% CI:0.77–0.84). A PREMASS score >0.23 showed 91.3% sensitivity (95% CI:79.79–100) and 80.46% specificity (95% CI:72.13–88.79) for >10% wt loss with an overall 55.26% positive predictive value (PPV) (95% CI:39.45–71.07) and 97.22% negative predictive value (NPV) (95% CI:93.43–100) and a relative risk (RR) of 19.90 (95% CI:4.93–80.37). In the validation cohort, PREMASS showed 76.47% sensitivity (95% CI:56.31–96.63) and 75.47% specificity (95% CI:63.89–87.06) with an overall 50% PPV (95% CI:30.78–69.22) and 90.91% NPV (95% CI:82.41–99.4) and a RR of 5.5 (95% CI: 2–15.10). Conclusions PREMASS is the first validated index for weight loss risk stratification in the following 12 months in SSc. Prediction of future weight loss in SSc could aid both in clinical management and stratification/enrichment in clinical trials. Disclosure of Interest None declared

Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination. In the last few years, adenosine receptors have been studied as a target for many diseases, including neurodegenerative conditions. The aim of this study was to investigate the effects of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate the Wnt pathway, we wanted to study PDRN effects on Wnt signaling following SCI. Spinal trauma was induced by extradural compression of spinal cord at T5-T8 level in C57BL6/J mice. Animals were randomly assigned to the following groups: Sham (n = 10), SCI (n = 14), SCI+PDRN (8 mg/kg/i.p.; n = 14), SCI+PDRN+DMPX (8 and 10 mg/kg/i.p., respectively; n = 14). DMPX was used as an adenosine receptor antagonist to evaluate whether adenosine receptor block might prevent PDRN effects. PDRN systemically administered 1 h following SCI, protected from tissue damage, demyelination, and reduced motor deficits evaluated after 10 days. PDRN also reduced the release of the pro-inflammatory cytokines TNF-α and IL-1β, reduced BAX expression and preserved Bcl-2. Furthermore, PDRN stimulated Wnt/β-catenin pathway and decreased apoptotic process 24 h following SCI, whereas DMPX administration prevented PDRN effects on Wnt/β-catenin signaling. These results confirm PDRN anti-inflammatory activity and demonstrate that a crosstalk between Wnt/β-catenin signaling is possible by adenosine receptors activation. Moreover, these data let us hypothesize that PDRN might promote neural repair through axonal regeneration and/or neurogenesis.

The aim of the study was to evaluate whether a reduced pain threshold is associated with increased temporomandibular dysfunction in systemic sclerosis (SSc) compared to psoriatic arthritis (PsA) and healthy controls. Ninety subjects participated in the study (30 SSc, 30 PsA, and 30 healthy controls). The Helkimo index was used to evaluate temporomandibular dysfunction. Digital palpation was performed at the temporomandibular joint (TMJ) surface and at the superficial masseter muscle (SMM) and pain intensity was recorded on a visual analog scale (VAS), while pain pressure threshold (PPT) was measured at the same sites through a pressure algometer. PPT scores were lower in SSc patients compared to PsA patients and controls. In addition, the average Helkimo index score, measuring the degree of TMJ dysfunction, was higher in SSc compared to PsA and controls. A significant inverse correlation was observed between every PPT score, and both Helkimo index and VAS palpation in SSc and PsA. Both the range of motion and all the other pain-related subdomains of the Helkimo index score (pain on movement, pain palpation TMJ and pain palpation muscle) were significantly worse in SSc compared to PsA, while no significant differences were observed in the TMJ function subdomain. In SSc patients, the skin score was directly associated with the range of motion subdomain of the Helkimo index. Our results confirm that TMJ function is impaired in SSc; further longitudinal studies are needed to assess the role of pain threshold in the assessment of limitations in TMJ function and to identify an objective marker of therapeutic response.

The authors present a case of a 51-year-old woman with clinical diagnosis of mixed connective tissue disease and overlap systemic lupus erythematosus features, with a 6-month history of progressive painless abdominal distension. On examination, evident signs of ascites were present. Both the abdominal-pelvic ultrasound and CT scan confirmed a large amount of ascites. A diagnostic paracentesis was performed, which revealed typical features of chylous ascites (CA). An extensive diagnostic work-up led by a multidisciplinary team was performed, excluding malignancy, cirrhosis, infectious, as well as cardiac and primary lymphatic causes. The patient was kept under surveillance, with dietary therapy and periodic ascitic drainages. The hypothesis of an autoimmune cause for CA was considered by exclusion. Rituximab therapy was initiated and an excellent response was achieved, with reduction of the rate of accumulation of CA and an increase in quality of life of the patient.

Several lines of evidence support the relevance of reactive oxygen species (ROS) in vitiligo, but the exact role of glycation and oxidation of macromolecules needs to be better addressed. To investigate the involvement of advanced oxidation protein products (AOPPs) and advanced glycation end-products (AGEs), we performed a case-control association study by spectrofluorimetry and spectrophotometry, in 47 patients with non-segmental generalized vitiligo and 47 age- and sex-matched controls. Significantly higher levels of both AOPPs (p

Pain perception and threshold show complex interactions with the inflammatory, psychiatric and neuroendocrine stimuli. This study aims to test whether lower serum cortisol levels are associated with lower pain thresholds and higher degree of depression in systemic sclerosis (SSc) and major depression with atypical features (MD-AF) patients compared to controls. 180 female subjects (SSc = 60, MD-AF = 60, healthy controls = 60) participated in this observational, cross-sectional, parallel group study. Pressure pain threshold (PPT) was assessed in three anatomical sites: nail bed (NB), metacarpophalangeal joint (MCP) and quadriceps muscle (QDR). Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) scale and morning serum cortisol levels were collected. In SSc patients, quality of life was measured through the Health Assessment Questionnaire (HAQ-DI) and the scleroderma-specific visual analogue scales (scleroderma-VAS). Lower PPT scores (NB 4.42 ± 1.6; MCP 4.66 ± 1.4; QDR 4.79 ± 1.5) were observed in SSc patients compared to both MD-AF (NB 7.33 ± 2.2; MCP 6.01 ± 1.9; QDR 6.31 ± 1.6; p

Background Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular alterations and autoimmune activation leading to widespread organ fibrosis. At the early stage of disease when organ involvement and extent of disease are emerging, mast cells may have some role, as implied by both symptoms and histologic evidence. Case presentation A female patient diagnosed with cutaneous mastocytosis experienced the onset of systemic sclerosis after 15 years followed by the switch of mastocytosis to the systemic phenotype. A literature review on the evidences related to mast-cells activation in systemic sclerosis is presented below. Conclusions For clinicians, more attention must be paid to the potential association between systemic sclerosis and cancer. This case suggests that a proliferative disease in the mast cell compartment—though representing a rare association—may not be completely unexpected in SSc and perhaps excess mast cell activity can serve a pathogenic role in promoting fibrotic disease.

Aims Systemic sclerosis (SSc) is characterized by vasculopathy and organ fibrosis. Although microvascular alterations are very well characterized, structural and functional abnormalities of large vessels are not well defined. Therefore, we evaluated the effect of simvastatin administration on aortic and small renal arteries thickening, and on myofibroblasts differentiation in a murine model of SSc. Methods and results SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl, 100 μl) for 6 weeks. Mice (n = 23) were randomized to receive: HOCl (n = 10); HOCl plus simvastatin (40 mg/kg; n = 8); or vehicle (n = 5). Simvastatin administration started 30 min after HOCl injection, and up to week 6. Aortic and small renal arteries intima-media thickness was evaluated by histological analysis. Immunostaining for α-smooth muscle actin (SMA), vascular endothelial growth factor receptor 2 (VEGFR2), and CD31 in aortic tissues was performed to evaluate myofibroblast differentiation and endothelial markers.In HOCl-treated mice, intima-media thickening with reduced lumen diameter was observed in the aorta and in small renal arteries and simvastatin administration prevented this increase. Aortic and renal myofibroblasts count, as expressed by α-SMA + density, was lower in the group of mice treated with simvastatin compared to HOCl-treated mice. Simvastatin prevented the reduction in VEGFR2 and CD31 expression induced by HOCl. Conclusions The administration of simvastatin regulates collagen deposition in the aortic tissues and in the small renal arteries by modulating myofibroblasts differentiation and vascular markers. Further studies are needed to better address the effect of statins in the macrovascular component of SSc.

Objectives. This trial aimed to test the effectiveness of a wearable pulsed electromagnetic fields (PEMF) device in the management of pain in knee OA patients. Methods. In this randomized [with equal randomization (1:1)], double-blind, placebo-controlled clinical trial, patients with radiographic evidence of knee OA and persistent pain higher than 40 mm on the visual analog scale (VAS) were recruited. The trial consisted of 12 h daily treatment for 1 month in 60 knee OA patients. The primary outcome measure was the reduction in pain intensity, assessed through VAS and WOMAC scores. Secondary outcomes included quality of life assessment through the 36-item Medical Outcomes Study Short-Form version 2 (SF-36 v2), pressure pain threshold (PPT) and changes in intake of NSAIDs/analgesics. Results. Sixty-six patients were included, and 60 completed the study. After 1 month, PEMF induced a significant reduction in VAS pain and WOMAC scores compared with placebo. Additionally, pain tolerance, as expressed by PPT changes, and physical health improved in PEMF-treated patients. A mean treatment effect of −0.73 (95% CI − 1.24 to − 0.19) was seen in VAS score, while the effect size was −0.34 (95% CI − 0.85 to 0.17) for WOMAC score. Twenty-six per cent of patients in the PEMF group stopped NSAID/analgesic therapy. No adverse events were detected. Conclusion. These results suggest that PEMF therapy is effective for pain management in knee OA patients and also affects pain threshold and physical functioning. Future larger studies, including head-to-head studies comparing PEMF therapy with standard pharmacological approaches in OA, are warranted. Trial registration: ClinicalTrials.gov, http://www.clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01877278","term_id":"NCT01877278"}}NCT01877278