Hydrogen peroxide is a neuronal alarmin that triggers specific RNAs, local translation of Annexin A2, and cytoskeletal remodeling in Schwann cells

Schwann cells are key players in neuro-regeneration: They sense "alarm" signals released by degenerating nerve terminals and differentiate toward a proregenerative phenotype, with phagocytosis of nerve debris and nerve guidance. At the murine neuromuscular junction, hydrogen peroxide (H2O2) is a key signal of Schwann cells' activation in response to a variety of nerve injuries. Here we report that Schwann cells exposed to low doses of H2O2 rewire the expression of several RNAs at both transcriptional and translational levels. Among the genes positively regulated at both levels, we identified an enriched cluster involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family. We show that both Annexin A2 (Anxa2) transcript and protein accumulate at the tips of long pseudopods that Schwann cells extend upon H2O2 exposure. Interestingly, Schwann cells reply to this signal and to nerve injury by locally translating Anxa2 in pseudopods, and undergo an extensive cytoskeleton remodeling. Our results show that, similarly to neurons, Schwann cells take advantage of local protein synthesis to change shape and move toward damaged axonal terminals to facilitate axonal regeneration

AB0462 BEHCET'S DISEASE: CLINICAL FEATURES AND OFF-LABEL BIOLOGIC TREATMENT STRATEGIES

Background:The treatment of Behçet's disease (BD) is still mainly based on the evidence derived from case reports, case series, retrospective analyses, and few clinical trials suggesting the safety and potential efficacy of off-label use of biologic agents in refractory cases.1Objectives:To describe clinical manifestations and their management, with particular focus on treatment indications, outcomes and safety of biologic therapy, in a cohort of patients with BD.Methods:Patients with a diagnosis of BD who visited our outpatient clinic until December 2019 were included in the study. Clinical data were recorded since diagnosis until the latest follow-up visit, analyzing clinical features, flares and therapeutic strategies adopted.Results:A total of 95 patients were included in the study with a medium follow-up of 108.54 ± 169.59 months. 20 of them (21. 05%) were treated with biologic agents. Patients treated with biologic therapy compared to those on conventional non-biologic therapies had a higher proportion of musculoskeletal (80% vs 46.67%, p = 0.008), neurological (30% vs 10.67%, p = 0.031), intestinal involvement (40% vs 12%, p = 0.004), and they were treated with a higher dose of glucocorticoids at diagnosis (16.84 mg ±14.01 vs 8.89 mg ± 11.76, p = 0.012). The most frequent indications for biologic step-up therapy were musculoskeletal involvement (40%), eye involvement (25%), neurological involvement (15%) and intestinal involvement (10%). Most patients initiated a biologic treatment within the first year of follow-up. TNF-inhibitor (TNFi) were more frequently prescribed (95%) and one patient was treated with 8 therapeutic cycles of Rituximab (500 mg/weekly for 4 infusions to be repeated after at least 6 months) because of recurrent pancytopenia. All patients experienced non-biologic therapy before starting a TNFi. The preferred first-line TNFi was infliximab (50%), followed by adalimumab (40%) and etanercept (5%). As second line treatment were also prescribed certolizumab (10%) and golimumab (5%). 10 patients switched to a second line treatment because of inefficacy of the first biologic agent, mainly because of refractory arthritis, intestinal and mucocutaneous involvement. One patient switched from infliximab to certolizumab during pregnancy with subsequent worsening of arthritis.85% of patients treated with biologic agents reached a clinical remission by the time of the latest follow up visit without any safety or tolerability issues.Conclusion:A relevant proportion of patients in our BD cohort were treated with biologic therapy, because of severe or refractory manifestations. The most frequent indications were musculoskeletal, neurological or intestinal involvement. Biologic agents were a generally effective and safe therapeutic approach.References:[1]F. Alibaz-Oner, M. H. Sawalha, H. Direskeneli. Management of Behçet disease, Curr. Opin. Rheumatol, 2018Table 1.General characteristics and disease involvement at diagnosisBiologic therapyNo biologic therapyp value20 (21.05%)75 (78.95%)General characteristicsMediaSDMediaSDAge at disease onset(years ± SD)34.5± 10.4938.64± 13.18p = 0.1976Diagnostic delay(months ± SD)45.28± 67.4828.09± 48.42p = 0.1996Glucocorticoids at diagnosis (mg prednisone ± SD)16.84± 14.018.89± 11.76p = 0.0115Glucocorticoids at latest follow up visit (mg prednisone ± SD)6.38± 7.763.83± 4.81p = 0.0707N%N%F / M12 / 860 / 4054 / 4172 / 28p = 0.3030Disease involvement at diagnosisOral ulcers2010075100Genital ulcers11553749,33p = 0.6540Cutaneous lesions15755066,67p = 0.4787Eye involvement6302736p = 0.6184Musculoskeletal involvement16803546,67p = 0.0082Neurological involvement630810,67p = 0.0311Intestinal involvement840912p = 0.0039Thrombosis2101824p = 0.1747Disclosure of Interests:None declare

POS0575 THE PATIENT GLOBAL ASSESSMENT (PGA) OF DISEASE ACTIVITY COLLECTS DIFFERENT INFORMATION IN EARLY COMPARED TO ESTABLISHED RHEUMATOID ARTHRITIS

Background:The patient global assessment (PGA) is the most widely used patient-reported measure in rheumatoid arthritis (RA), being a component of disease activity scores and definitions of remission. Studies have however shown that, at least in established RA, PGA is mostly associated with pain, functional limitation, psychological distress and comorbidities, rather than with objective measures of inflammation. As such, the inclusion of PGA as a driver of intensification of immunosuppressive therapy is been questioned. Determinants of PGA may however differ in the earliest stages of RA, when pain processing mechanisms and damage accrual have not occurred yet. Whether the association of PGA with disease activity in RA changes over time is at present undetermined.Objectives:To analyze the associations between PGA and disease activity measures in patients with RA across different phases of the disease.Methods:1.002 RA patients from two independent cohorts were included: 1) a prospective longitudinal cohort of early RA (5 years) (n=401) with inadequate response to methotrexate. Determinants of PGA were assessed by Pearson's correlation coefficients and multivariable linear regression.Results:In early RA, median (IQR) symptom duration at inclusion was 15 (9-27) weeks, 71.5% of the patients were female, 49.3% were autoantibody-positive, and 30% had radiographic evidence of ≥1 erosion. The mean (SD) DAS28 was 4.94 (1.19), and the mean (SD) PGA 57.6 (26.6). The proportion of patients at least in low disease activity (DAS28 0.40) at all time points, and were independent of other co-variates (Table 1). Swollen joints (SJC28) were independently and directly associated with PGA at all time points until 12 months, whilst the association become indirect at 24 months (Table 1). In ACPA-positive patients, PGA at 6 and 12 months was weakly but still significantly associated with SJC28 even in low disease activity states (adj r 0.15 and 0.13, p<0.05). Patients with established RA had a mean [SD] DAS28 of 5.3 [1.2] and were ACPA-positive in 69.6% of the cases. Independent determinants of PGA were pain, HAQ and tender joints, whilst no associations with SJC28 and acute phase reactants were found neither in the overall cohort nor in ACPA-positive patients.Conclusion:In established RA, PGA appears mostly related to factors outside the core domains of disease activity. In contrast, in the early phases of the disease, PGA may more strictly collect information on inflammatory-related symptoms. Better understanding of the relationship between patient reported outcomes and disease activity in the various phases of RA may thus be needed before introducing definitive changes in the current definitions of disease activity.References:[1]Nikiphorou E et al. Arthritis Res Ther 2016;18:251[2]Ferreira RJO et al. Ann Rheum Dis 2019;78:e109.Table 1.Associations of PGA in early RA at different time points0 months6 months12 months24 monthsr (95% CI)pr (95% CI)pr (95% CI)pr (95% CI)pVAS pain0.74 (0.70-0.77)<0.0010.83 (0.80-0.86)<0.0010.84 (0.80-0.86)<0.0010.83 (0.79-0.87)<0.001HAQ0.47 (0.41-0.54)<0.0010.54 (0.46-0.62)<0.0010.57 (0.50-0.63)<0.0010.50 (0.41-0.59)<0.001SJC280.27 (0.19-0.35)<0.0010.27 (0.18-0.35)<0.0010.21 (0.12-0.30)<0.0010.23 (0.13-0.33)<0.001TJC280.34 (0.27-0.41)<0.0010.39 (0.31-0.47)<0.0010.39 (0.30-0.46)<0.0010.30 (0.20-0.40)<0.001CRP0.08 (0.00-0.17)0.050.09 (0.00-0.19)0.070.19 (0.10-0.28)<0.0010.03 (0.09-0.14)0.63β standpβ standpβ standpβ standpVAS pain0.66<0.0010.76<0.0010.74<0.0010.80<0.001HAQ0.20<0.0010.180.010.200.030.220.003SJC280.170.030.150.040.110.04----TJC28----------------CRP------------Acknowledgements:I have no acknowledgements to declare.Disclosure of Interests:Ludovico De Stefano: None declared, Serena Bugatti Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos, Bernardo D'Onofrio: None declared, Ennio Favalli Speakers bureau: AbbVie, MSD, Novartis, Pfizer, UCB Pharma, Antonio Manzo: None declared, Roberto Caporali Speakers bureau: AbbVie, BMS, Celgene, HSD, Lilly, Pfizer, Roche, UCB Pharma, Carlomaurizio Montecucco Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos, Roche, Novarti

Milwaukee shoulder syndrome (apatite associated destructive arthritis): therapeutic aspects

Milwaukee shoulder is a well defined clinical entity that can be observed in particular in older women. It is a destructive arthropathy associated with the deposition of calcium pyrophosphate dihydrate cristals, characterized by the presence of large amount of synovial fluid and a complete tear of the rotator cuff. Clinical features include pain, swelling and progressive functional impairment. The first-line treatment include the use of analgesic drugs and repeated arthrocentesis followed by intra-articular steroid administration; closed-needle tidal irrigation has been reported to be useful. In late phase we can observe narrowing of the acromion-humeral and of the gleno-humeral joint and progressive degenerative changes at the humeral head, leading to almost complete functional impairment. In these cases a surgical approach with total shoulder arthroplasty may be considered

ANALISIS INTERDEPENDENSI FOREIGN DIRECT INVESTMENT (FDI) DENGAN VARIABEL MAKRO EKONOMI

ABSTRAK Tujuan utama dari penelitian ini adalah untuk menganalisis interdependensi antara FDI dengan beberapa variabel yang lain, seperti PDB, Trade, Nilai Tukar, dan Tingkat bunga. Model VAR digunakan untuk menunjukkan pandangan yang komprehensif dari interdependensi ini. Hasil empiris menunjukkan bahwa melalui model VAR, interdependensi antara variabel FDI, PDB, Trade, Nilai Output Industri, Nilai Tukar dan Tingkat Suku Bunga telah diteliti dalam hubungan jangka panjang melalui kointegrasi vektor dan jangka pendek yang berdampak pada model VAR. Korelasi dinamis variabel telah diperoleh dengan analisis varian dan analisis respon impuls. Beberapa implikasi besar muncul dari hasil penelitian. Jika pemerintah Indonesia berkeinginan mendorong FDI dan pertumbuhan ekonomi, hal ini dapat dilakukan dengan output dan nilai tukar. Dalam jangka pendek maupun jangka panjang, keduanya sangat penting untuk stabilitas ekonomi. Kata Kunci : FDI, Pertumbuhan ekonomi, variabel makro dan model VARBanda Ace