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Riccardo Terribili,1 Silvia Grazzini,1 Edoardo Conticini,1 Paolo Falsetti,1 Giovanni Biasi,1 Claudia Fabiani,2 Luca Cantarini,1 Bruno Frediani1 1Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; 2Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, ItalyCorrespondence: Edoardo Conticini, Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy, Email conticini.edoardo@gmail.comObjective: Tocilizumab (TCZ) is the only biologic drug approved for the treatment of giant cell arteritis (GCA), having clinical trials and real-life studies proved its efficacy and safety. However, the optimal duration of the treatment has yet to be determined, being its early interruption associated with an increased risk of relapse. Conversely, prolonged schemes of therapy may rise safety concerns. The aim of the study was to evaluate the incidence of adverse events (AEs) and remission/relapse rate in a cohort of GCA patients treated with TCZ and an accelerated steroid tapering scheme, followed for 24 months.Methods: We retrospectively included patients referring to our clinic from January 2019 to November 2021 who were diagnosed with GCA and started subcutaneous TCZ treatment (162 mg/week). They also received up to 62,5 mg of prednisone (PDN), tapered following an accelerated six-month scheme.Results: We collected 38 patients, with a mean age of 76,4 years, treated with TCZ for an average of 22,3 months. AEs occurred in 11 (29%) subjects, and only one serious AE was reported; 7 (18%) patients permanently discontinued TCZ. At the end of the follow-up, all the patients continuing treatment showed clinical remission, with a PDN dosage < 5mg. We registered 3 (8%) minor relapses under TCZ, after an average of 15 months.Conclusion: Our data support the evidence of a safe and effective long-term use of TCZ in GCA patients, especially when combined with moderate GCs doses for the shortest possible duration.Keywords: giant cell arteritis, vasculitis, tocilizumab, biological therapy, safety

Silvia Grazzini,1,&ast; Edoardo Conticini,1,&ast; Paolo Falsetti,1 Miriana D’Alessandro,2 Jurgen Sota,1 Riccardo Terribili,1 Caterina Baldi,1 Claudia Fabiani,3 Elena Bargagli,2 Luca Cantarini,1 Bruno Frediani1 1Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; 2Respiratory Diseases and Lung Transplant Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; 3Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy&ast;These authors contributed equally to this workCorrespondence: Edoardo Conticini, Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, AOUS Le Scotte, viale Mario Bracci 14, Siena, 53100, Italy, Email conticini.edoardo@gmail.comIntroduction: No head-to-head study has assessed the superiority of tocilizumab versus methotrexate in giant cell arteritis (GCA), and few studies have demonstrated its effectiveness in terms of ultrasonographic findings, but without a control group. The primary endpoint was to assess whether tocilizumab was superior to methotrexate in inducing normalization of US findings, whereas the secondary endpoint was to assess the effectiveness of precocious withdrawal of glucocorticoids.Methods: We prospectively enrolled all the patients with active GCA at our clinic. The inclusion criteria were clinical diagnosis of GCA; active disease; and clinical, laboratory, and US data, evaluated using the halo count (HC) and OMERACT GCA Ultrasonography Score (OGUS). Evaluations were repeated at 3, 6, and 12 months.Results: Twenty patients were treated with Tocilizumab and 9 with Methotrexate. All but three tocilizumab-treated patients achieved remission at six months, whereas at 12 months, all patients were in glucocorticoid-free remission. Up to three of the nine methotrexate patients experienced a lack of efficacy or minor relapses. Tocilizumab-treated patients showed a statistically significant difference between baseline and all follow-ups in terms of OGUS and HC, whereas the difference in the Methotrexate group was significant after 1 year. The mean glucocorticoid dosage significantly decreased in both groups. No severe adverse events or major relapses were reported.Conclusion: Our study demonstrates the superiority in terms of rapidity of a tocilizumab-based scheme over a methotrexate-based scheme in inducing clinical and US remission. Precocious withdrawal of glucocorticoids did not increase the risk of relapse.Keywords: GCA, giant cell arteritis, methotrexate, tocilizumab, ultrasonography, vasculitis

Objective: Idiopathic inflammatory myopathies (IIM) are rare autoimmune diseases that primarily affect striated muscles; skin, joints, and lungs may be involved with different degrees of severity. Traditional treatment relies on high-dose glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs., Methods: A growing amount of evidence is demonstrating the potential role of novel treatments in the management of IIM. We report our experience with Janus kinase inhibitors (JAKi) in these conditions and review the current evidence for the use of small molecules in real-life clinical practice., Results: A total of 41 papers were retrieved from PubMed, 37 papers concerning IIM and JAKi, and 4 papers concerning IIM and apremilast., Conclusions: An overall good efficacy was evidenced in IIM-associated skin lesions, including rash, ulcers, and calcinosis. If present, muscle and joint involvement demonstrated a good response to therapy, while it was not possible to draw any conclusion about dysphagia. No life-threatening adverse events were reported.

Introduction: Anti-synthetase syndrome (ASS) is a rare autoimmune disease characterized by the presence of anti-aminoacyl-transfer-RNA synthetase antibodies (ARS) and the involvement of muscles, skin, joints, and lungs. Despite increasing interest and evidence, optimal clinical management remains unclear due to a lack of randomized control trials. This study aims to evaluate the efficacy and safety of a treatment regimen involving early co-administration of glucocorticoids and immunosuppressants, with rapid prednisone tapering., Materials and Methods: We prospectively enrolled patients referred to our multidisciplinary "Myositis Clinic" with a diagnosis of ASS. Clinical, serological, instrumental and medications data were collected at baseline and at 6 and 12 months follow-up. According to treatment protocol, patients were treated with traditional synthetic immunosuppressants or rituximab (RTX) depending on clinical manifestations. Prednisone (PDN) was gradually tapered and eventually discontinued within 6 or 12 months., Results: A total of twenty-seven subjects were enrolled: arthritis, myositis and ILD were assessed in 9, 16 and 18 patients, respectively, and all of them had an active disease. RTX was administered after methotrexate (MTX) in 4 cases of refractory joint involvement and co-administration of a second immunosuppressant was necessary in 2 patients. When muscle involvement was present, first-line therapy was MTX, followed by mycophenolate mofetil (MMF) or RTX, which allowed to achieve low disease activity or remission, respectively. Eight ILD-patients were treated with MMF and switched to RTX in 5 cases of inefficacy, but all patients were in clinical remission at the end of follow-up. At 12 months, 12 patients discontinued PDN., Conclusions: This study is the first to prospectively report on the efficacy and safety of a stepwise, steroid-sparing treatment ASS encompassing various domains. MTX, as well as other synthetic immunosuppressants, showed limited efficacy in ASS-related arthritis, while RTX emerged as a promising option. This study recommends early RTX use in case of arthritis, suggesting it as a pivotal treatment for ILD too, and raises questions regarding maintenance therapy and treatment-free remission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Takayasu's arteritis is a rare large vessel vasculitis typically affecting young Asian women. It causes inflammation of the aorta and its major branches, leading to stenosis and aneurysmal dilations, and increasing cardiovascular morbidity due to accelerated atherosclerosis. Although glucocorticoids are effective for acute disease control and preliminary data on immunosuppressive drugs are promising, standardized treatment protocols are lacking. The use of prophylactic treatments with antihypertensives, antiplatelets, anticoagulants, and lipid-lowering drugs to prevent thrombotic and ischemic complications remains debated. This study reviews the evidence on the effectiveness of non-immunosuppressive medical therapy in Takayasu's arteritis. A search of the PubMed database identified eleven studies involving 204 patients. Antiplatelets: data on 68 patients were mixed, in fact low-dose aspirin did not prevent major cardiovascular events in 36 patients, but higher doses reduced ischemic complications in 24 patients. Anticoagulants: no data on new oral anticoagulants were available, and vitamin K antagonists in 9 patients did not alter cardiovascular complications. Antihypertensives: ACE-inhibitors controlled blood pressure in patients with renovascular hypertension but increased the risk of acute renal function decline, while β-blockers reduced the symptoms and the progression of myocardial hypertrophy in patients with heart failure and aortic regurgitation. Statins: data from two cohorts showed that while statins reduced the recurrence rate of arteritis in 30 patients, they did not affect recurrence rates or cardiovascular complications in 13 patients. Overall, current evidence, although not definitive, supports the use of non-immunosuppressive medical treatments to prevent long-term complications and damage in Takayasu's arteritis, considering the disease's pathophysiological mechanisms and increased cardiovascular risk. Further research is strongly encouraged., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Ultrasound has a paramount role in the diagnostic assessment of giant cell arteritis (GCA); Southend halo score (HS), halo count (HC), and OMERACT GCA Ultrasonography Score (OGUS) are the first quantitative scores proposed in this setting. The aim of this study was therefore to assess the diagnostic accuracy of these scores in a real-life scenario, as well as to evaluate their optimal cutoff, also with respect to disease extent, sex, and age., Methods: We retrospectively collected clinical, serological, and US findings of all patients referred for the first time to our vasculitis clinic in the suspicion of GCA., Results: A total of 79 patients were included, and a definite diagnosis of GCA was made in 43 patients. For OGUS, the ROC curve showed an optimal cut point of 0.81 (sensitivity 79.07% and specificity 97.22%). For HC and HS, the optimal cutoff values were > 1.5 (sensitivity 76.7% and specificity 97.2%) and > 14.5 (sensitivity 74.4% and specificity 97.2%), respectively. No relevant differences were assessed when patients were stratified according to disease extent, age, and sex. Compression sign (CS) was positive in 34 of 38 patients with cranial GCA and negative in all controls and LV-GCA., Conclusion: All three scores display good sensitivity and excellent specificity, although the cutoff was slightly different than proposed. In particular, for OGUS, a threshold of 0.81 could be employed for diagnostic purposes, although it was developed solely for monitoring. Due to its high sensitivity and specificity, CS should be always assessed in all patients referred with a suspicion of cranial GCA., 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 © 2024 Conticini, Falsetti, Al Khayyat, Grazzini, Baldi, Bellisai, Gentileschi, Bardelli, Fabiani, Cantarini, Dasgupta and Frediani.)

To assess the rate of PMR who, during the follow-up, undergo a diagnostic shift as well as to assess which clinical, laboratory and US findings are associated to a diagnostic shift and predict the long-term evolution of PMR. All PMR followed-up for at least 12 months were included. According to the US procedures performed at diagnosis, patients were subdivided into four subgroups. Clinical data from follow-up visits at 12, 24, 48 and 60 months, including a diagnostic shift, the number of relapses and immunosuppressive and steroid treatment, were recorded. A total of 201 patients were included. During the follow-up, up to 60% had a change in diagnosis. Bilateral LHBT was associated with persistence in PMR diagnosis, whereas GH synovitis and RF positivity to a diagnostic shift. Patients undergoing diagnostic shift had a higher frequency of GH synovitis, shoulder PD, higher CRP, WBC, PLT and Hb and longer time to achieve remission, while those maintaining diagnosis had bilateral exudative LHBT and SA-SD bursitis, higher ESR, lower Hb and shorter time to remission. Cluster analysis identified a subgroup of older patients, with lower CRP, WBC, PLT and Hb, lower PD signal or peripheral synovitis who had a higher persistence in PMR diagnosis, suffered from more flares and took more GCs. Most PMR have their diagnosis changed during follow-up. The early use of the US is associated with a lower dosage of GCs. Patients with a definite subset of clinical, laboratory and US findings seem to be more prone to maintain the diagnosis of PMR., (© 2023. The Author(s).)

Background: Anti-cytosolic 5'-nucleotidase 1A (anti-cN1A) antibodies were proposed as a biomarker for the diagnosis of inclusion body myositis (IBM), but conflicting specificity and sensitivity evidence limits its use. Our study aimed to assess the diagnostic accuracy of anti-cN1A in a cohort of patients who underwent a myositis line immunoassay for suspected idiopathic inflammatory myopathies (IIM). We also assessed the agreement between two testing procedures: line immunoassay (LIA) and enzyme-linked immunoassay (ELISA)., Materials and Methods: We collected retrospective clinical and serological data for 340 patients who underwent a myositis antibody assay using LIA (EUROLINE Autoimmune Inflammatory Myopathies 16 Ag et cN-1A (IgG) line immunoassay) and verification with an anti-cN1A antibody assay using ELISA (IgG) (Euroimmun Lubeck, Germany)., Results: The serum samples of 20 (5.88%) patients (15 females, 5 males, mean age 58.76 ± 18.31) tested positive for anti-cN1A using LIA, but only two out of twenty were diagnosed with IBM. Seventeen out of twenty tested positive for anti-cN1A using ELISA (median IQR, 2.9 (1.9-4.18))., Conclusions: Our study suggests excellent concordance between LIA and ELISA for detecting anti-cN1A antibodies. LIA may be a rapid and useful adjunct, and it could even replace ELISA for cN1A assay. However, the high prevalence of diseases other than IBM in our cohort of anti-cN1A-positive patients did not allow us to consider anti-cN1A antibodies as a specific biomarker for IBM.

Objectives: Data on the safety of anti-SARS-CoV-2 vaccines in patients with rare rheumatic diseases, such as systemic vasculitis (SV), are limited. The aim of this study was to evaluate the occurrence of a disease flare and the appearance of adverse events (AEs) following administration of anti-SARS-CoV-2 vaccine in a multicentre cohort of patients with SV., Methods: Patients with SV and healthy controls (HC) from two different Italian rheumatology centres were asked to complete a questionnaire assessing disease flares occurrence, defined as new onset of clinical manifestations related to vasculitis needing an implementation of therapy, and local/systemic AEs appearance following anti SARS-CoV-2 vaccination., Results: 107 patients with SV (57 ANCA-associated) and 107 HC were enrolled. A disease flare occurred in only one patient (0.93%) with microscopic polyangiitis after the first dose of an mRNA vaccine. After both the first and the second vaccine dose administration, no significant differences in AEs between patients with SV and HC were observed; no serious AEs were reported as well., Conclusions: These data suggest a good risk profile for anti-SARS-CoV-2 vaccine in patients with systemic vasculitis.

Purpose: Temporal (TA) and axillary (AXA) arteries Color Doppler Ultrasonography (CDUS) is the most reliable diagnostic technique for the diagnosis of giant cell arteritis (GCA), displaying high sensitivity and specificity. Nevertheless, CDUS is still poorly performed in the common clinical practice, being employed only by rheumatologists with a relevant expertise in this field. Color Doppler Eye Ultrasound (CDEUS) is a procedure variously employed in ophthalmology and preliminary findings have displayed a possible role also in the diagnostic work-up of GCA. Aim of this study was to assess whether CDEUS may play a role in the differential diagnosis between arteritic and non-arteritic blindness., Methods: We prospectively included all patients evaluated since September 2021 to May 2022 by our Ophthalmology Unit for sudden blindness and referred to our Vasculitis Clinic in the suspicion of GCA. All patients underwent complete ophthalmological evaluation, routine blood tests, AxA and TA CDUS and CDEUS. According to the definite diagnosis, patients were divided in the following subgroups: (A) patients suffering from arteritic central retinal artery occlusion (CRAO), (B) patients suffering from non-arteritic CRAO, (C) patients suffering from arteritic anterior ischemic optic neuropathy (AION), (D) patients suffering from non-arteritic AION., Results: During the observational period, we included a total of 25 patients suffering from sudden blindness and referred to Vasculitis Clinic for ruling out GCA. Patients belonging to group A showed no flow or reduced flow within the territory of central retinal artery (CRA), no "spot sign" and positive TA CDUS; on the other hand, patients from group B presented normal TA CDUS, no flow or reduced flow within the territory of CRA and the presence of "spot sign". Conversely, no relevant difference was evidenced at CDEUS in patients with and without arteritic AION., Conclusion: Our preliminary data displayed a good reliability of CDEUS in distinguishing between arteritic and non-arteritic CRAO, while no difference was assessed between arteritic and non-arteritic AION. Since AION represents the most common presentation of cranial GCA, CDEUS does not seem a reliable procedure in the diagnostic work-up of GCA and should be restricted only to the exclusion of thrombo-embolic occlusions within the territory of central retinal artery., (© 2022. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Objectives: Rituximab (RTX) is an anti-CD20 chimeric monoclonal antibody recommended as off-label treatment in patients with idiopathic inflammatory myopathies (IIM). The present study aimed to evaluate changes in immunoglobulin (Ig) levels during RTX-treatment and their potential association with infections in a cohort of IIM patients., Methods: Patients evaluated in the Myositis clinic belonging to the Rheumatology Units of Siena, Bari and Palermo University Hospitals, and treated for the first time with RTX were enrolled. Demographic, clinical, laboratory and treatment variables, including previous and concomitant immunosuppressive drugs and glucocorticoid (GC) dosage were analysed before (T0) and after 6 (T1) and 12 (T2) months of RTX treatment., Results: Thirty patients (median age, IQR 56 (42-66); 22 female) were selected. During the observational period, low levels of IgG (<700 mg/dl) and IgM (<40 mg/dl) occurred in 10% and 17% of patients, respectively. However, no one showed severe (IgG<400 mg/dl) hypogammaglobulinaemia. IgA concentrations were lower at T1 than T0 (p=0.0218), while IgG concentrations were lower at T2 compared to those at baseline (p=0.0335). IgM concentrations were lower at T1 and T2 than T0 (p<0.0001), as well at T2 than T1 (p=0.0215). Three patients suffered major infections, two others had paucisymptomatic COVID-19, one suffered from mild zoster. GC dosages at T0 were inversely correlated with IgA T0 concentrations (p=0.004, r=- 0.514). No correlation was found between demographic, clinical and treatment variables and Ig serum levels., Conclusions: Hypogammaglobulinaemia following RTX is uncommon in IIM and is not related to any clinical variables, including GC dosage and previous treatments. IgG and IgM monitoring after RTX treatment does not seem useful in stratifying patients who require closer safety monitoring and prevention of infection, due to the lack of association between hypogammaglobulinaemia and the onset of severe infections.

Objectives: No clear-cut guidelines exist for the use of imaging procedures for the diagnosis of idiopathic inflammatory myopathies (IIM). The aim of the present study was to assess the diagnostic accuracy of power Doppler ultrasonography (PDUS) score in IIM patients compared with a control group and its usefulness during follow-up., Methods: All patients evaluated in the Vasculitis and Myositis Clinic, Rheumatology Unit, University of Siena were prospectively collected. All patients underwent US examination of both thighs in axial and longitudinal scans, which were also performed twice (T1) or three times (T2)., Results: Forty-five patients with IIM (median [interquartile range] age 55 [45-66] years; 35 female) were enrolled. Receiver operating characteristic curves distinguished patients and controls based on ∑power Doppler (PD), ∑oedema, ∑atrophy and CRP. The best cut-off value for ∑PD was 0.5, ∑oedema 1.5, ∑atrophy 0.5 and CRP 0.22 mg/dl. In a logistic regression analysis, the variables that most influenced diagnosis of IIM were ∑PD and ∑oedema (P = 0.017 and P = 0.013, respectively). ∑Oedema was lower at T1 (P = 0.0108) and T2 (P = 0.0012) than at T0. Likewise, ∑PD was lower at T1 (P = 0.0294) and T2 (P = 0.0420) than at T0. Physician global assessment was lower at T1 (P = 0.0349) and T2 (P = 0.0035) than at baseline., Conclusion: Our findings show that PDUS is a reliable diagnostic tool in the differential diagnosis between inflammatory and non-inflammatory myopathies. Moreover, PDUS can be employed also during the follow-up of patients with IIM. A reduction in disease activity, measured by physician global assessment, led to a concomitant decrease in both oedema and PD, which was directly correlated with their rate of change. This underlines the close link between clinical assessment and PDUS findings, not only at diagnosis but also during monitoring., (© 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.)

Idiopathic inflammatory myopathies (IIM) are a group of different conditions typically affecting striate muscle, lung, joints, skin and gastrointestinal tract. Treatment typically relies on glucocorticoids and synthetic immunosuppressants, but the occurrence of refractory, difficult to treat, manifestations, may require more aggressive treatment, borrowed from other autoimmune diseases, including biologic disease modifying drugs (bDMARDs). In this regard, we conducted a systemic literature review in order to depict the current evidence about the use of bDMARDs in IIM. A total of 78 papers, published during the last 21 years, were retrieved. The majority of patients was treated with TNF-α inhibitors, whose effectiveness was assessed particularly in recalcitrant striate muscle, skin and joints involvement. Rituximab, whose evidence is supported by a large number of real-life studies and trials, seems to be an excellent option in case of ILD and anti-synthetase syndrome, while Tocilizumab, despite not meeting primary and secondary endpoints in a recently published clinical trial, proved its effectiveness in rapidly progressing ILD. Similarly, Abatacept, studied in a phase IIb clinical trial with conflicting evidence, was reported to be effective in some case reports of refractory dermatomyositis. Less data exist for anti-IL1 and anti-IL23 agents, which were employed particularly for inclusion body myositis and severe skin disease, respectively. This study provides an organ-focused assessment of bDMARDs in IIM, which display encouraging results in the treatment of refractory subsets of disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategy to curb the coronavirus disease-19 (COVID-19) pandemic. The present study described the clinical status of patients affected by idiopathic inflammatory myopathies (IIM) after COVID-19 vaccination to assess the number of relapses. We included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. They underwent a telephone survey. A total of 119 IIM patients (median, IQR 58 (47-66) years; 32males; 50 dermatomyositis, 39 polymyositis and 30 anti-synthetase syndrome) were consecutively enrolled. Except four patients who refused the vaccination, 94 (81.7%) received Comirnaty, 16 (13.9%) Spikevax, 5 (4.4%) Vaxzevria. Seven (6.1%) patients had flare after vaccination. One of them had life-threatening systemic involvement and died two months after second dose of COVID-19 vaccination. From logistic regression analysis, Chi 2 -log ratio = 0.045,the variable that most influences the development of flare was the number of organs involved (p = 0.047). Sixty-eight patients received the third dose of COVID-19 vaccination: 51(75%) Comirnaty and 17 (25%) Moderna. No patients had flares after third dose. Our study represents the largest cohort of IIM patients in which the incidence of recurrence after anti-SARS-CoV-2 vaccine was assessed. In line with real-life data from other diseases, we found a clinical non-statistically significant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease., (© 2022. The Author(s).)

Caregivers are responsible for respecting the privacy of the elderly, who are more vulnerable. This requires an individual and collective professional reflection on the meaning of the practices. It is also about respecting the free choice of lifestyle by taking into account the needs of family caregivers., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)