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Maurizio Benucci,1 Arianna Damiani,2 Francesca Li Gobbi,1 Valentina Grossi,3 Maria Infantino,3 Mariangela Manfredi,3 Laura Niccoli,4 Fabrizio Cantini4 1Rheumatology Unit, Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro, Florence, Italy; 2Rheumatology Unit, University of Florence, Florence, Italy; 3Immunology and Allergology Laboratory Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro, Florence, Italy; 4Rheumatology Unit, S. Stefano Hospital, Azienda USL-Toscana Centro, Prato, ItalyCorrespondence: Maurizio BenucciRheumatology Unit, Azienda Sanitaria USL-Toscana Centro, Hospital S. Giovanni di Dio, Via Torregalli 3, Florence 50143, ItalyTel +39-055-6932636Fax +39-055-6932099Email maurizio.benucci@uslcentro.toscana.itAbstract: Over the last 20 years, the greatly improved knowledges of underlying pathogenic mechanisms of AS, including the role of tumor necrosis factor (TNF), the interleukin 23/Th17 axis, and interleukin-17 (Il-17), constituted the rationale to develop biologics selectively inhibiting these pathways. For more than 10 years, anti-TNF biologics were successfully employed to treat AS, with marked improvement of signs and symptoms in around 60% of the patients. Recent knowledge of the pathophysiology of spondyloarthritis has highlighted the emerging role of the IL-17/IL-23 axis. New therapies with selective biological drugs have emerged in the treatment of this pathology. In this review, we evaluated the effects of ixekizumab, a new anti–IL-17A, that was licensed both by EMA and FDA in August 2019 for the treatment of ankylosing spondylitis. The review highlights the efficacy and safety data of the 3 randomized controlled trials (COAST V-COAST W-COAST X) and those of the extension to 52 weeks of COAST V and COAST W.Keywords: ixekizumab, ankylosing spondylitis, randomized control trials

Maurizio Benucci,1 Arianna Damiani,1 Mariangela Manfredi,2 Maria Infantino,2 Valentina Grossi,2 Francesca Li Gobbi11Rheumatology Unit, S.Giovanni di Dio Hospital, Florence, Italy; 2Immunology and Allergology Laboratory Unit, S.Giovanni di Dio Hospital, Azienda USL-Toscana Centro, Florence, ItalyAbstract: Rheumatoid arthritis (RA) is a chronic inflammatory disorder that affects joints with swelling and progressive joint destruction. The pathology leads to a progressive disability with an impact on the quality of life of the patients. Strategies to reduce in-patient care costs could have a considerable impact on lowering the direct medical costs of RA in Italy. Abatacept, a selective T-cell costimulation modulator, is a valuable treatment option for patients with moderate-to-severe RA. A search using the keywords “cost-effectiveness analysis", "budget impact model", "abatacept", and "rheumatoid arthritis” was carried out on PubMed. Abatacept in the first- and second-treatment lines has been evaluated in our research. We evaluated patients with inadequate MTX response, inadequate anti-TNF agents response, switch studies and real-world data. Furthermore, in our research, we evaluated the main head-to-head studies published.Keywords: abatacept, budget impact model, cost-effectiveness analysis, rheumatoid arthritis

Maurizio Benucci,1 Francesca Bandinelli,1 Arianna Damiani,1 Francesca Li Gobbi,1 Maria Infantino,2 Valentina Grossi,2 Mariangela Manfredi2 1Rheumatology Unit, Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro, Florence, Italy; 2Immunology and Allergology Laboratory Unit, Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro, Florence, Italy Background: Rheumatoid arthritis patients are exposed to a high risk of cardiovascular morbidity and mortality even in the early phases of the disease. Methods: We evaluated carotid common carotid intimal media thickness (ccIMT) intimal thickness and brachial flow-mediated dilation (FMD) of 45 rheumatoid arthritis patients without known cardiovascular risk factors or heart disease on a stable dose of prednisone 5.2±1.2 mg/day and Methotrexate 11.5±2.1 mg at baseline (T0) and after 12 months (T1) of treatment with Abatacept 125 mg/week. The comparison between T0 and T1 (t- and Mann–Whitney test), correlation (Spearman r), and predictivity (linear regression) of FMD, ccIMT vs clinical and laboratory parameters (disease activity 28 score, tumor necrosis factor alpha [TNFα], interleukin-6, erythrocyte sedimentation rate, C-reactive protein (CRP), CD3+, CD3+/CD4+, CD3+/CD8+, CD19+(B), CD20+(B), NK CD3-CD56+CD16+, CD14+ HLA DR+, CD4+CD28+, CD4+CD28, rheumatoid factor IgM, IgA, RF IgG, anti-citrullinated peptide antibodies) were also evaluated. Results: During Abatacept treatment, ccIMT and FMD remained stable and disease activity 28 score, CRP, erythrocyte sedimentation rate, and interleukin-6 decreased significantly (p=0.0001, 0.002, 0.0002, 0.0001 respectively). At T0, only ccIMT resulted as correlated with baseline TNFα values (p=0.0245) in an inverse proportion. At T1, ccIMT correlated with CD3/CD8+ lymphocytes number (p=0.0351) and FMD with CRP (p=0.0075). In regression analysis, baseline ccIMT and FMD had a low predictivity for TNFα (p=0.011) and CRP (p=0.049) at T1, respectively. Conclusion: This study shows that the endothelial function remained stable during Abatacept treatment. Keywords: Abatacept, rheumatoid arthritis, cardiovascular disease

Maurizio Benucci,1 Arianna Damiani,1 Francesca Li Gobbi,1 Francesca Bandinelli,1 Maria Infantino,2 Valentina Grossi,2 Mariangela Manfredi,2 Guillaume Noguier,3 Francesca Meacci2 1Rheumatology Unit, 2Immunology and Allergology Laboratory Unit, USL-Toscana Centro, Hospital S. Giovanni di Dio, Florence, Italy; 3Theradiag, Croissy Beaubourg, France Introduction: The aim of this study was to investigate the correlation between human leukocyte antigen (HLA) haplotypes and the development of antidrug antibodies (ADAs) in a cohort of patients with rheumatic diseases.Patients and methods: We evaluated the presence of ADAs in 248 patients with inflammatory rheumatic diseases after 6 months of treatment with anti-TNF drugs: 26 patients were treated with infliximab (IFX; three with rheumatoid arthritis [RA], 13 with ankylosing spondylitis [AS], 10 with psoriatic arthritis [PsA]); 83 treated with adalimumab (ADA; 24 with RA, 36 with AS, 23 with PsA); 88 treated with etanercept (ETA; 35 with RA, 27 with AS, 26 with PsA); 32 treated with certolizumab (CERT; 25 with RA, two with AS, five with PsA); and 19 treated with golimumab (GOL; three with RA, seven with AS, nine with PsA). Serum drug and ADA levels were determined using Lisa-Tracker Duo, the ADA-positive samples underwent an inhibition test, and the true-positive samples underwent genetic HLA typing. To have a homogeneous control population, we also performed genetic HLA typing of 11 ADA-negative patients.Results: After inhibition test, the frequency of ADAs was 2/26 patients treated with IFX (7.69%), 4/83 treated with ADA (4.81%), 0/88 treated with ETA (0%), 4/32 treated with CERT (12.5%), and 1/19 treated with GOL (5.26%). The frequency of HLA alleles in the examined patients was HLA-DRβ-11 0.636, HLA-DQ-03 0.636, and HLA-DQ-05 0.727. The estimated relative risks between the ADA-positive patients and the ADA-negative patients were HLA-DRβ-11 2.528 (95% CI 0.336–19.036), HLA-DQ-03 1.750 (95% CI 0.289–10.581), and HLA-DQ-05 2.424 (95% CI 0.308–15.449). Conclusion: This is the first study that shows an association between HLA and genetic factors associated with the occurrence of ADAs in patients with rheumatic diseases, but the number of samples is too small to draw any definite conclusion. Keywords: antidrug antibodies, HLA haplotypes, rheumatic diseases

Maurizio Benucci,1 Francesca Meacci,2 Valentina Grossi,2 Maria Infantino,2 Mariangela Manfredi,2 Emanuele Bellio,2 Valerio Bellio,2 Francesca Li Gobbi,1 Laura Bazzichi,3 Paolo Moscato,4 Dario Caputo,4 Gianantonio Saviola,5 Rossella Talotta,6 Piercarlo Sarzi-Puttini,6 Fabiola Atzeni71Rheumatology Unit, Ospedale San Giovanni di Dio, Florence, Italy; 2Allergology and Immunology Laboratory, Ospedale San Giovanni di Dio, Florence, Italy; 3Rheumatology Unit, University of Pisa, Pisa, Italy; 4Internal Medicine and Rheumatology Unit, University of Salerno, Salerno, Italy; 5Rheumatology Unit, Salvatore Maugeri Foundation, Mantua, Italy; 6Rheumatology Unit, Ospedale Luigi Sacco, Milan, Italy; 7IRCCS Galeazzi Orthopedic Institute, Milan, ItalyAbstract: The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26–83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of >3.2, an erythrocyte sedimentation rate (ESR) of >30 mm/hour, and CRP levels of >1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of 10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of 10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show that the occurrence of anti-drug antibodies against TCZ is very rare and that there are statistically significant correlations between TCZ levels of >10 µg/mL and ESR, CRP levels, and DAS28.Keywords: tocilizumab, TCZ drug level, antibodies anti-TCZ

Recent progress on the development of a new solid state detector allowed the use of finely pixelled photocathodes obtained from silicon semiconductors. SiPM detectors seem to be an ideal tool for the detection of Cherenkov and fluorescence light in spite of their not yet resolved criticism for operating temperature and intrinsic noise. The main disadvantage of SiPM in this case is the poor sensitivity in the wavelength range 300-400 nm, where the Cherenkov light and fluorescence radiation are generated. We report on the possibility to realize a new kind of pixelled photodetector based on the use of silicon substrate with carbon nanotube compounds, more sensitive to the near UV radiation. Also if at the very beginning, the development of such detector appears very promising and useful for astroparticle physics, both in the ground based arrays and in the space experiments. The detectors are ready to be operated in conditions of measurements without signal amplification.

This article critically explores neoliberal administrative priorities and the ways in which they shape and constrain academic language and learning (ALL) advisory practice in the Australian higher education sector. Drawing on semi-structured interview data collected from in-service ALL advisors working in Australian universities, we highlight a disjuncture between the participants' understandings of effective practice and the institutional framing of ALL advisory work as a mechanism to improve accessibility of higher study and retention of diversifying student cohorts. The data indicate the potential for institutional priorities to generate dilemmas in advisors' daily practice as they are tasked with performing support via formats considered antithetical to meeting students' needs and fostering productive approaches to study. Under these circumstances, participants characterised collaboration between advisors and content specialists in the pursuit of more embedded approaches as dependent on individual endeavours and stymied by a lack of institutional support. We call for renewed consideration of the formats and affordances with which advisors work in order to better align ALL advisory practice with the holistic development of students' academic literacy skills.