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Clinical examination (CE) and musculoskeletal ultrasound (MSUS) of ten joints (knee, ankle, wrist, elbow, II-MCP) and their extra-articular (EA) compartments (tendons and bursae) were performed on 35 consecutive patients with active juvenile idiopathic arthritis (JIA) (active group) to test how the extension of MSUS examinations to EA changes the concordance between MSUS and CE. The overall concordance between CE and MSUS, measured with Cohen’s Kappa (k), was moderate (k = 0.43); the addition of EA MSUS increased the concordance in all joints, with the exclusion of II-MCP (k = 0.49). In the ankle and wrist, the k increase was relevant (k from 0.13 to 0.27 and 0.11 to 0.41). In the active group patients, we observed 44 subclinical synovitis; the number of subclinical synovitis per patient was correlated with JADAS-27 (p = 0.03) and was higher in a control group composed of 15 patients with persistent disease remission (1.3 vs. 0.4 p = 0.03). Our results show that EA compartments should always be evaluated during MSUS. Furthermore, we demonstrate a moderate concordance between CE and MSUS in JIA; the finding of subclinical synovitis is common in patients with active diseases and is related to disease activity.

Statin-associated autoimmune myopathy is a rare muscle disorder, characterized by autoantibodies against HMGCR. The anti-HMGCR myopathy persists after statin, and often requires immunosuppressive therapy. However, there is not a standardized therapeutic approach. The purpose of this study is to report the effectiveness of the immunosuppressive treatment employed in a multi-center and multi-disciplinary cohort of patients affected by anti-HMGCR myopathy, in which an immunoglobulin (IVIG)-based treatment strategy was applied. We collected 16 consecutive patients with a diagnosis of anti-HMGCR myopathy, between 2012 and 2019, and recorded data on clinical and laboratory presentation (i.e., muscle strength, serum CK levels, and anti-HMGCR antibody titer) and treatment strategies. Our results highlight the safety and efficacy of an induction therapy combining IVIG with GCs and/or methotrexate to achieve persistent remission of the disease and steroid-free maintenance. Under IVIG-based regimens, clinical improvement and CK normalization occurred in more than two thirds of patients by six months. Relapse rate was low (3/16) and 2/3 relapses occurred after treatment suspension. Nearly 90% of the patients who successfully discontinued GCs were treated with a triple immunosuppressive regimen. In conclusion, an IVIG-based regimen, which particularly includes high-dose immunoglobulin, GCs and methotrexate, can provide a fast remission achievement with GC saving.

IMPORTANCE: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. OBJECTIVE: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao(2)/Fio(2)) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. INTERVENTIONS: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. MAIN OUTCOME AND MEASURES: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao(2)/Fio(2) ratio less than 150 mm Hg, whichever came first. RESULTS: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao(2)/Fio(2) ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37

Objective To determine the intra- and inter-observer reliability of ultrasound (US)-detected age-related joint vascularization and ossification grading in healthy children. Methods Following standardized image acquisition and machine setting protocols, 10 international US experts examined four joints (wrist, second metacarpophalangeal joint, knee, and ankle) in 12 healthy children (divided into four age groups: 2–4, 5–8, 9–12, and 13–16 years). Grey-scale was used to detect the ossification grade, and power Doppler (PD) US was used to detect physiological vascularization. Ossification was graded from grade 0 (no ossification) to grade 3 (complete ossification). A positive PD signal was defined as any PD signal inside the joint. Kappa statistics were applied for intra- and inter-observer reliability. Results According to the specific joint and age, up to four solitary PD signals (mean, 1.5) were detected within each joint area with predominant localization of the physiological vascularization in specific anatomic positions: fat pad, epiphysis, physis, and short bone cartilage. The kappa values for ossification grading were 0.87 (range, 0.85–0.91) and 0.58 for intra- and inter-observer reliability, respectively. The bias-adjusted kappa values for intra- and inter-observer reliability were 0.71 (range, 0.44–1.00) and 0.69, respectively. Conclusion Detection of normal findings (i.e., grading of physiological ossification during skeletal maturation and identification of physiological vessels) can be highly reliable by using clear definitions and a standardized acquisition protocol. These data will permit development of a reliable and standardized US approach for evaluating paediatric joint pathologies. This article is protected by copyright. All rights reserved.

Introduction Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). Objectives The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset. Materials and methods A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed. Results One-hundred and six patients were included (median age at onset of 55 years [IQR 42–67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13–77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4–9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51–13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality. Conclusions Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.

ObjectivesTo define the correlation between joint ultrasonography and clinical examination in patients with juvenile idiopathic arthritis (JIA) and to assess whether synovitis detected by ultrasonography in clinically inactive patients predicts arthritis flares.Methods88 consecutive patients with JIA—46 (52%) with persistent oligoarthritis, 15 (17%) with extended oligoarthritis, 15 (17%) with rheumatoid factor-negative polyarthritis and 12 (14%) with other forms of JIA, all clinically inactive for a minimum of 3 months—underwent ultrasound (US) assessment of 44 joints. Joints were scanned at study entry for synovial hyperplasia, joint effusion and power Doppler (PD) signal. Patients were followed clinically for 4 years.ResultsUS was abnormal in 20/88 (22.7%) patients and in 38/3872 (0.98%) joints. Extended oligoarthritis and rheumatoid factor-negative polyarthritis were more frequent in US-positive than in US-negative patients (35.0% vs 11.8% and 30.0% vs 13.2%, respectively; P=0.005). During 4 years of follow-up, 41/88 (46.6%) patients displayed a flare; 26/68 (38.2%) were US-negative and 15/20 (75%) were US-positive at baseline. Abnormality on US examination, after correction for therapy modification, significantly increased the risk of flare (OR=3.8, 95% CI 1.2 to 11.5). The combination of grey scale and PD abnormalities displayed a much higher predictive value of relapse (65%, 13/20) than grey scale alone (33%, 6/18).ConclusionsUS abnormalities are a strong predictor of relapse at individual patient level. Irrespective of treatment, the risk of flare in US-positive versus US-negative patients was almost four times higher. In case of US abnormalities, patients should be carefully followed regardless of both the International League of Associations for Rheumatology and Wallace categories.

Background Interstitial lung disease (ILD) evaluation is challenging, given the low sensitivity of X-ray and pulmonary function tests, and limited accessibility and radiation linked to repetitive HRCT. Lung Ultrasound (US) has shown potential in the evaluation of ILD of autoimmune diseases including systemic sclerosis. Objectives To define and asses the reliability of definitions of US-detected findings in ILD. Methods A taskforce (TF) within the OMERACT US WG performed a literature review (LR) to identify US lesions in ILD, a Delphi exercise to define these lesions and a web-based exercise to test the reliability of these definitions by using either intraclass correlation coefficient (ICC) or kappa statistics. Prior to the Delphi exercise all participants received training files and were subsequently asked to provide clips on BL, PLI and normal findings. Based on the results of the LR, which identified B-lines (BL) and pleural line irregularity (PLI) as main US findings in ILD, the Delphi exercise contained statements on US definitions on BL and PLI. After reaching agreement (> 75%) on the above mentioned items, a set of 80 high-quality clips (30 for PLI, 50 for BL), was selected and distributed to the TF members in order to score them (semiquantitatively, 0-2 for PLI and total number for BL) Results The 3 Delphi rounds and the web-based exercise were completed by 24 and 22 sonographers, respectively. Final definitions are reported in Table I. The web-based exercise showed moderate inter-reader reliability for both BL (ICC=0.61) and PLI (kappa=0.69). Table I: definitions of PLI and BL Pleural line irregularity (PLI): a loss of regularity that may be associated with an increase in thickness, focal, diffuse, or nodular B-line (BL): a vertical hyperechoic reverberation artifacts that arise from the pleural line, extend to the bottom of the screen without fading, and move synchronously with lung sliding Conclusion US is a candidate imaging modality to identify and monitor ILD in rheumatic diseases; US consensus based definitions of main US findings were defined and endorsed. Further development is planned for validating US as an outcome measurement instrument for ILD. Disclosure of Interests Andrea Delle Sedie Speakers bureau: Abbvie, UCB, Celgene, MSD, Lene Terslev Speakers bureau: Speakers fee from : Roche, Novartis, Pfizer, MSD, BMS, Celgene, George Bruyn : None declared, Tomas Cazenave: None declared, stavros chrysidis: None declared, Mario Diaz: None declared, Marco Di Carlo: None declared, Marilena Frigato: None declared, Luna Gargani: None declared, Marwin Gutierrez: None declared, ALOJZIJA HOCEVAR: None declared, Annamaria Iagnocco: None declared, Aaron Juche: None declared, Peter Mandl: None declared, Esperanza Naredo Consultant for: Abbvie, Speakers bureau: AbbVie, Roche, Bristol-Myers Squibb, Pfizer, UCB, Lilly, Novartis, Janssen, and Celgene GmbH, Mohammed A Mortada: None declared, Carlos Pineda: None declared, Francesco Porta: None declared, Viviana Ravagnani: None declared, Carlo Alberto Scire: None declared, Teodora Serban: None declared, Kate Smith: None declared, Maria Stoenoiu Grant/research support from: Abbvie, Roche, Wyeth, Marika Tardella: None declared, Karina Torralba: None declared, Richard Wakefield: None declared, Maria-Antonietta d’Agostino: None declared

Background:Anti-3-hydroxy-3-methylglutaryl-coenzime A reductase (HMGCR) myopathy is a new entity, which has been clearly associated to statin use, even if it can be diagnosed in patients without a history of exposure to statin or even in the childhood (1).Objectives:The aim of the study is to describe the efficacy of a triple therapy regimen consisting in high-doses of intravenous immunoglobulins (IVIG), methotrexate (MTX), and glucocorticoids (GC) in 16 patients with Anti-HMGCR myopathy enrolled in 6 specialized centres.Methods:A total of 16 patients with anti-HMGCR myopathy (7 females; 9 males) were collected. Mean (±standard deviation) age at the onset of disease was 72.4±10.3 years old. All patients were diagnosed having anti-HMGCR myopathy [anti-HMGCR antibodies were measured by chemiluminescence assay (BioFlash, Inova, CA)] (2). Median follow-up was 29.5 months (interquartile range: 15.75-60 months). Anti-HMGCR antibodies were available in the follow-up in 8/16 patients.Results:Thirteen out of 16 patients (81.3%) had been exposed to statin (1/13 to red rice), 3/16 (18.7%) were not exposed. As induction therapy, 11/16 patients have been treated with triple therapy (high-dose IVIG, MTX and GC), 2/16 with double therapy (high-dose IVIG and GC), 2/16 have been treated with GC alone, the patient exposed to red rice resolved only with red rice suspension. Clinical remission and normalization of CPK values within month +24 were obtained in all the patients. All the patients were in remission at the last follow-up. Gradual improvement started soon from the first month, and among the 13 patients treated with an aggressive immunosuppresssive therapy including IVIG (13/13), GC (13/13) and methotrexate (11/13), 9/13 normalized the CPK value within 6 months. Clinical and laboratory response was accompanied by significant decrease or normalization of the anti-HMGCR antibody titer. All the patients were either not taking GC (56.3%), or were taking low doses of GC (43.7%) at the last follow-up. Four patients had stopped GC within 6 months. No serious side effects were recorded. After persistent remission, a maintenance immunosuppressive therapy was then administered. Only 3 relapses in 3 different cases were recorded, all of them during drug-free remission in long-term follow-up. Reinduction was again effective in all.Conclusion:Anti-HMGCR myopathy is a rare and serious myopathy which usually affects older people during statin treatment. After statin suspension, a rapid and sustained remission can be achieved by induction with a triple aggressive therapy consisting in medium-to high doses of GC, high-dose IVIG, and MTX (3). GC should be tapered as soon as possible. Relapse appears infrequent during maintenance treatment. Monitoring anti-HMGCR antibody titer may be clinically relevant.References:[1]AL Mammen et al. N Engl J Med. 2016;374:664-9[2]Musset L et al. Autoimmun Rev. 2016;15:983-93.[3]Aggarwal A et al. Scand J Rheumatol. 2019; 1-7.Acknowledgments:We thank MD Francesca Grosso and MD Valentina Mecheri from the University of Florence, MD Angela Zuppa and MD Chiara De Michelis, from San Martino Hospital, Genova, for their valued collaboration in data collectionDisclosure of Interests:Elena Treppo: None declared, Maria Infantino: None declared, Maurizio Benucci: None declared, Viviana Ravagnani: None declared, Boaz Palterer: None declared, Marina Grandis: None declared, Martina Fabris: None declared, Paola Tomietto: None declared, Mariangela Manfredi: None declared, Arianna Sonaglia: None declared, Maria Grazia Giudizi: None declared, Francesca Ligobbi: None declared, Daniele Cammelli: None declared, Paola Parronchi: None declared, Salvatore De Vita Consultant of: Roche, GSK, Speakers bureau: Roche, GSK, Novartis, Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer

Background Diffuse alveolar haemorrhage (DAH) is a rare and severe manifestation of ANCA-associated vasculitides (AAV). Objectives To identify predictors of survival in patients with AAV-DAH. Methods A retrospective study of 102 consecutive patients (50% females; mean age 59±17 years) from 27 Italian Centres diagnosed with AAV-DAH was planned. Cox regression unadjusted analyses were performed. Results Among AAV patients, 47% had Granulomatosis with Polyangiitis (GPA), 47% Microscopic Polyangiitis (MPA) and 6% Eosinophilic Granulomatosis with Polyangiitis (EGPA). At DAH onset, mean BVAS was 20±8 and most patients had renal involvement (RI). Admission to Intensive Care Unit was needed in 27% of patients, while ventilatory support (VS) was required in 46%. At least one cardiovascular risk factor (CVRF) was recorded in 48%. Over a median follow-up of 39 months (25%–75% IQR 66 months), 19/102 patients (18.6%) died (figure 1). All patients received high-dose glucocorticoids in association with Cyclophosphamide (CYC 78%, mean cumulative dose 8±7 g) or Rituximab (37%). Plasma exchange was performed in 46%. Infections occurred in 38%. Age>65 years (HR 3.05 [95% CI 1.18–7.9], p=0.04), CVRF ≥2 (HR 8.85 [95% CI [AG7] 2.34–33.50], p=0.01), BVAS (v.3) (HR 1.07 [95% CI 1.01–1.13], p=0.01) were associated with mortality, whereas FFS was not. The need for VS (HR 4.54 [95% CI 1.48–13.85], p=0.008) and infections (HR 3.98 [95% CI 1.48–10.69] were also associated with mortality. Conclusions Older age, VS, CVRF and infections affect the survival in AAV. There is a need for specific outcome measeures. Disclosure of Interest None declared

Objective.To provide an update from the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group on the progress for defining ultrasound (US) minimal disease activity threshold at joint level in rheumatoid arthritis (RA) and for standardization of US application in juvenile idiopathic arthritis (JIA).Methods.For minimal disease activity, healthy controls (HC) and patients with early arthritis (EA) who were naive to disease-modifying antirheumatic drugs were recruited from 2 centers. US was performed of the hands and feet, and scored semiquantitatively (0–3) for synovial hypertrophy (SH) and power Doppler (PD). Synovial effusion (SE) was scored a binary variable. For JIA, a Delphi approach and subsequent validation in static images and patient-based exercises were used to developed preliminary definitions for synovitis and a scoring system.Results.For minimal disease activity, 7% HC had at least 1 joint abnormality versus 30% in the EA group. In HC, the findings of SH and PD were predominantly grade 1 whereas all grades were seen in the EA cohort, but SE was rare. In JIA, synovitis can be diagnosed based on B-mode findings alone because of the presence of physiological vascularization. A semiquantitative scoring system (0–3) for synovitis for both B-mode and Doppler were developed in which the cutoff between Doppler grade 2 and grade 3 was 30%.Conclusion.The first step has been taken to define the threshold for minimal disease activity in RA by US and to define and develop a scoring system for synovitis in JIA. Further steps are planned for the continuous validation of US in these areas.

Objectives Musculoskeletal ultrasonography (US) has the potential to be an important tool in the assessment of disease activity in childhood arthritides. To assess pathology, clear definitions for synovitis need to be developed first. The aim of this study was to develop and validate these definitions through an international consensus process. Methods The decision on which US techniques to use, the components to be included in the definitions as well as the final wording were developed by 31 ultrasound experts in a consensus process. A Likert scale of 1-5 with 1 indicating complete disagreement and 5 complete agreement was used. A minimum of 80% of the experts scoring 4 or 5 was required for final approval. The definitions were then validated on 120 standardized US images of the wrist, MCP and tibiotalar joints displaying various degrees of synovitis at various ages. Results B-Mode and Doppler should be used for assessing synovitis in children. A US definition of the various components (i.e. synovial hypertrophy, effusion and Doppler signal within the synovium) was developed. The definition was validated on still images with a median of 89% (range 80-100) of participants scoring it as 4 or 5 on a Likert scale. Conclusions US definitions of synovitis and its elementary components covering the entire pediatric age range were successfully developed through a Delphi process and validated in a web-based still images exercise. These results provide the basis for the standardized US assessment of synovitis in clinical practice and research. This article is protected by copyright. All rights reserved.

Background According to literature arthritis is a rare complication following parasitic infection. In the italian pediatric population parasitic infection is manly caused by Enterobius Vermicularis; it is often asymptomatic but common symptoms can be anal nocturnal itching, insomnia, irritability, abdominal pain together with arthralgia Objectives To describe cases of mono or poliarthritis due to parasitic infection in young patients followed at the Verona9s Pediatric Rheumathology Clinic from 2010 to 2016 Methods Medical records of 8 patients followed at the Pediatric Rheumatology were analyzed. The mean age of 8 patients was 8 (F:M 3:5). The following data were evaluated: anamnesis data, clinical symptoms (anal itching, irritability, arthralgia, abdominal pain and arthritis), Blood test and scotch tape test. All patients underwent joint ultrasound (US). Physical symptoms of joint9s involvement were evaluated in all children by an experienced rheumatologist. Results 6 patients had symmetrical poliathirtis, 2 patients had monoarthritis (knee and hand). Symptom9s complaint were systemic (12,5%), abdominal (25%), and general pruritus (25%).Blood test confirmed high inflammation indices (25%) and hypereosinophilia (12,5%).Serological tests and stool investigations allowed to diagnose the following infections: Enterobius vermicularis (6 cases) giardia lamblia (1 case); dientaomeba fragilis (1 case).Joint US evidenced synovium hyperplasia in 75% of the cases and tenosynovitis in 50% of the cases.After appropriate antiparasitic treatment complete articular and systemic symptomatic remission was observed (100% cases); also joint US control normalized.2 cases, after about 6 months, were re-evaluated for arthritis relapse and in both cases a parasitic reinfection was confirmed. Conclusions Analysis of this series of patients underlines the following data: arthritis can be a manifestation of parasitic infection; treatment must be aimed against the parasite involved in order to achieve complete clinical and laboratory data remission; reinfection must always be considered in cases of relapse; differential diagnosis of this form of arthritis with other chronic polyarthritis is fundamental due to the risk of disseminated infection in case of immunosuppressive treatment Disclosure of Interest None declared

Background Ultrasound (US) was found to have face and content validity for detecting synovitis in juvenile idiopathic arthritis (JIA) with higher sensitivity than clinical examination. In order to test validity and improve the applicability of US in JIA, the OMERACT US pediatric subtask force recently published preliminary definitions for the sonographic features of synovitis in children. Objectives Aim of this study was to confirm and improve B-mode and color power/Doppler (PD) US definitions for synovial components and grading in children, by using an image and patient based exercise. Methods The definitions were confirmed and modified in a multi-step process. In the 1st step, definitions were developed in multi-round Delphi web based consensus process were ≥80% of participants would need to reach ≥80% of agreement on a Likert scale from 1–5 (1 strongly disagree, 2 disagree, 3 neutral, 4 agree, 5 strongly agree). In the 2nd step, in a face to face meeting, a subgroup of these experts revised the definitions for final wording and performed intra- and inter-observer reliability exercise study in JIA patients as the final 3rd phase of the process. The definitions were tested in four joints (wrist, 2nd MCP, knee and ankle) of JIA patients divided in four age groups following standardized image acquisition and machine setting protocol. Statistics program R (version 3.3.0) was used for the statistical analyses. For intra-rater agreement Cohen kappa and for inter-rater agreement prevalence and bias adjusted kappa (PABAK) were calculated if needed. Results Reliability exercise included 20 JIA patients (distributed in equal numbers by age groups), 14 observers, 4 joints/observer, 3 observers/joint, 360 intra- and 360 inter-observer tests. A 0–3 semi-quantitative B-mode and color power/Doppler US definitions for synovial components and grading, were agreed (presented in Figure 1). Conclusions The proposed synovitis grading for children showed to be reliable why the next step should be to test sensitivity to change in order to possibly be used as an outcome tool in JIA. Disclosure of Interest None declared

Objective To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA). Methods The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation-maximization algorithm, and BLyS serum levels were analyzed using enzyme-linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti–cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti–tumor necrosis factor (anti-TNF) agents had previously failed. In the whole series of seropositive patients in whom anti-TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77–117.39], P = 0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7–152.5], P = 0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2–7.8], P = 0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear. Conclusion BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti-TNF agents have failed.

The objective of this study was to evaluate the incidence of the most severe vascular complications, such as pulmonary arterial hypertension, scleroderma renal crisis, and digital necrosis requiring amputation, in a monocentric group of systemic sclerosis (SSc) patients cyclically treated with intravenous iloprost. We reviewed the record-charts of 115 patients affected by SSc (18 men and 97 women, mean age 58.9.1 ± 14.2 years) regularly receiving iloprost for at least 3 years; the mean duration of the treatment was 98.8 ± 37.5 months (a total of 946.8 years of therapy). Demographic and clinical features were recorded. None of the patients died of SSc-associated vascular complications. After iloprost administration digital gangrene requiring amputation developed in 2 patients who had concomitant peripheral arterial disease (a total of 3 episodes; annual incidence of 0.31 for 100 years of iloprost therapy). Four patients were diagnosed with pulmonary arterial hypertension during iloprost treatment (annual incidence of 0.42 for 100 years of drug therapy); in none of the cases did the complication show a progressive course. No cases of scleroderma renal crisis were observed. With the limits of an observational study and in the absence of a control group, our experience suggests that prolonged cyclic iloprost therapy may limit the incidence/progression of severe digital and visceral SSc-vasculopathy.

Musculoskeletal ultrasound (US) now thrives as an established imaging modality for the investigation and management of chronic inflammatory arthritis. We summarize here results of the Outcome Measures in Rheumatology (OMERACT) US working group (WG) projects of the last 2 years. These results were reported at the OMERACT 12 meeting at the plenary session and discussed during breakout sessions. Topics included standardization of US use in rheumatic disease over the last decade and its contribution to understanding musculoskeletal diseases. This is the first update report of WG activities in validating US as an outcome measure in musculoskeletal inflammatory and degenerative diseases, including pediatric arthritis, since the OMERACT 11 meeting.

Objective\ud \ud The role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region.\ud \ud Methods\ud \ud C5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method.\ud \ud Results\ud \ud Even though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases.\ud \ud Conclusions\ud \ud Our results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation.

OBJECTIVE: The polymorphism 158V/F of Fc fragment of IgG (FCGR) type 3A may influence the response to rituximab (RTX) in rheumatoid arthritis (RA). We investigated the FCG3A polymorphism in a large cohort of RA patients treated with RTX, also by considering the possible loss of response from month +4 to +6 after RTX and the presence of established predictors of response. METHODS: The study analysed 212 RA patients. European League Against Rheumatism (EULAR) response was evaluated at months +4 and +6 after the first RTX infusion. The FCGR3A polymorphism was analysed by PCR followed by Sanger sequencing. RESULTS: The FCGR3A genotypes were associated with EULAR response (good or moderate) at month +6 (response in 34/38 (89.5%) VV vs 70/106 (66%) VF and in 51/77 (66.2%) FF patients; p=0.01), but not at month +4 (response in 32/37 (86.5%) VV vs 69/102 (67.6%) VF and 53/73 (72.6%) FF patients; p=0.09). Loss of response was observed only in VF and FF carriers ((VV vs VF vs FF: 0/37 (0%) vs 11/102 (10.8%) vs 12/73 (16.4%); p=0.02)). Probability of response at month +6 was very high when at least two of the three following items selected by multivariate analysis were present: positive rheumatoid factor and/or anticyclic citrullinated peptide antibodies, previous treatment with ≤1 anti-tumor necrosis factor (TNF) agent, and 158VV FCGR3A genotype (p

OBJECTIVE: To find out whether a high number of auto-antibodies can increase the probability of a "good-EULAR response" and to identify the possible biomarkers of response in seropositive rheumatoid arthritis (RA) patients undergoing the B cell depletion therapy (BCDT). PATIENTS AND METHODS: One hundred and thirty-eight patients with long standing RA (LSRA), 75% non or poorly responsive to one or more TNFα blockers, all seropositive for at least one autoantibody (AAB) (RF-IgM, RF-IgA, RF-IgG, anti-MCV, ACPA-IgG, ACPA-IgA, ACPA-IgM) received one full course of BCDT. The major outcomes (moderate or good-EULAR response) were assessed after 6 months of therapy. The IL6 and BAFF levels were also determined. RESULTS: At a 6-month follow-up, 33 (23.9%) of the RA patients achieved a good EULAR response. Having up to 5-AABs positivity increased the chances for treatment response. After a logistic regression analysis, however, only 4 baseline factors arose as associated with a good-EULAR response: no steroid therapy (OR = 6.25), a lymphocyte count 52.1 IU/ml (OR = 8.37) and BAFF levels

Objective To assess fetal and maternal outcomes in women with systemic sclerosis (SSc). Methods Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2–193 months). Results SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (

Sir, We have read the letter by Belloli L et al. [1], who commented on our paper concerning low levels of vitamin D in patients affected by systemic sclerosis (SSc) [2] and showed further data on hypovitaminosis D in SSc. We agree with Belloli L et al. that in Italy, hypovitaminosis D is very frequent not only in systemic rheumatic diseases as SSc but also in very different unrelated diseases like osteoarthritis [1] as well as in elderly women [3], but not in premenopusal women, in whom low concentrations of vitamin D were found in 27.8% and 3.4% of the cases in winter and in summer, respectively [4]. But in our opinion, the interest concerning hypovitaminosis D in SSc and in other connective tissue diseases was that low levels of vitamin D may influence clinical manifestations; in SLE hypovitaminosis D has been associated with disease activity and severity [5–7] and in undifferentiated connective tissue diseases with a high risk of developing a well-defined connective tissue disease [8]. In rheumatoid arthritis, the serum concentration of vitamin D correlated negatively with disease activity (DAS28) and disability as evaluated by Health Assessment Questionnaire and mobility activities of daily living score [9]. In SSc, an inverse correlation between the serum level of vitamin D has been reported with disease activity and with acutephase reactants [10]; vitamin D deficiency was also associated with more severe diseases [2], supporting both the immunomodulatory properties [11] and the antifibrotic action of the vitamin [12, 13]. Moreover, very recently, it has been reported that vitamin D plays an antiproliferative effect on mesenchymal multipotent cells [14] revealing possible new perspectives on the pleiotropic properties of the molecule. As recently reviewed, the development of autoimmune rheumatic diseases is dependent on the interaction between genetic background and many environmental factors, which include hypovitaminosis D [15]. Therefore, low vitamin D status may represent an easily modifiable factor, whereby treatment may have a beneficial impact on both the development and the clinical phenotype of connective tissue diseases.

Vitamin D displays many extraosseous immunomodulatory effects. The aim of the study was to evaluate the level of vitamin D in patients with systemic sclerosis (SSc) and to analyze the associations between the concentration of the vitamin and clinical manifestations. In March-April 2009, 65 consecutive SSc patients underwent evaluation of vitamin D concentrations by the LIAISON immunoassay (normal 30-100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency, while concentrations

Background Lower activity of 11 beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) classically induces hypertension by leading to an altered tetrahydrocortisol- versus tetrahydrocortisone-metabolites (THFs/THE) shuttle. Recent cell culture and animal studies suggest a role for promoter methylation, a major epigenetic feature of DNA, in regulation of HSD11B2 expression. Little is known, however, of human HSD11B2 epigenetic control and its relationship with the onset of hypertension. Objective To explore the possible relevance of HSD11B2 promoter methylation, by examining human peripheral blood mononuclear cell (PBMC) DNA and urinary THFs/THE ratio as a biochemical indicator of 11beta-HSD2 activity, in blood pressure control. Methods Twenty-five essential hypertensives and 32 subjects on prednisone therapy were analyzed, the latter to investigate 11beta-HSD2 function in the development of hypertension. Results Elevated HSD11B2 promoter methylation was associated with hypertension developing in glucocorticoid-treated patients in parallel with a higher urinary THFs/THE ratio. Essential hypertensives with elevated urinary THFs/THE ratio also showed higher HSD11B2 promoter methylation. Conclusions These results show a clear link between the epigenetic regulation through repression of HSD11B2 in PBMC DNA and hypertension.

Background Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterised by arthritis of unknown origin with onset before age of 16 years. Patients may have high concentrations of positive antinuclear antibodies (ANA) and a high risk of developing chronic iridocyclitis. The chronicity of this illness can affected seriously psychological aspects of these young patients and their parents. Objectives To evaluate the level of stress among the parents of children affected by JIA and its correlation with the activity and duration of the disease. Methods 25 parents (mean age of the sons 12 years old) underwent PSI - SF: Parenting Stress Index” (Richard R. Abidin) evaluation; it is a 36 item test drawn in 3 scales to rule out parenting stress, parent and son interaction and eventually type of son according to the point of view of the parent (ie a son with various difficulties); the test may reveal a parental defencive attitude (i.e answers that suggest the creation of a better parental imagine than the reality). The score of the test according to the single scales and the total scale is converted into quintiles and the values above the 85th percentage are significant. The presence of a defencive attitude is confirmed by a score equal or below 10 points. Results 20% of the parents resulted affected by stress (5 out of 25) A defencive attitude was revealed in 36% of the cases (9 out of 25). 16% of the parents have a difficult interaction with their children (4 out of 25 with the mean age of the children 13,5 years old and a mean duration of the illness 5,4 years) 24% of the parents consider their sons having difficulties (6 out of 25 with the mean age of the children 10,8 years old and a mean duration of the illness 5 years). The overall stress is revealed in 28% of the young population (mean age 11,4 years old and a mean duration of the illness 5,7 years). There was no significant difference between the activity of the illness and the presence or not of ocular involvement. Conclusions Only few parents are stressed by their son diagnosis of JIA. There is however a significant defencive attitude among the parents maybe due to the negation of stress (difficulty of acceptance of a chronic illness?). Parenting stress seems to be higher in the teenage group; it is not worse according to the disease activity or to the presence of ocular involvement. JIA treatment should involve a mulidisciplinary team of caregivers (rheumatologists, pediatricians, phychologysts) in order to cure also the multifaceded psychological aspects of the illness and not least its acceptance by the young patient and by the family. Parental stress if not properly diagnosed and treated may compromise the overall treatment of the JIA as well as the psychological evolution of these young patients in such a critical phase of their life. Disclosure of Interest None declared

Background Musculoskeletal Ultrasound (MSUS) is commonly used to detect synovial inflammation in adults affected by inflammatory rheumatisms. MSUS in children is nowadays still a challenge. For this reason MSUS in JIA is still seldom known and used by pediatric rheumatologists. Objectives To study if grey scale (GSUS) and Power Doppler Ultrasound (PDUS) can better identify subclinical synovitis than physical examination and could be added to Wallace criteria of inactive disease (ID) to better identify JIA patients (pts) on Clinical Remission (CR). Methods 100 consecutive pts with JIA (age 18mo-25yrs) according to ILAR classification, with ID according to Wallace criteria, and 28 healthy controls were submitted to the MSUS of 42 joints (MCPs, PIPs, wrists, elbows, shoulders, hips, knees, ankles and MTPs). MSUS was performed immediately after clinical evaluation, by 3 trained sonographers (ODL, VR, AS), blinded to clinical findings, who recorded synovial hyperplasia, joint effusion and PDUS. Apparatus used: GE Logiq P5 with an 8-12MHz linear probe and Esaote MyLab 70 with a 6-18MHz linear probe. Intraobserver and interobserver reproducibility of US was assessed. In each joint, synovial hyperplasia/joint effusion were graded as follows: 0=absent, 1=mild, 2=moderate and 3=marked. PDUS was graded as follows: 0=absent, 1=presence of single vessel dot, 2=presence of confluent vessel dots in less than half of the synovial area and 3=presence of confluent vessel dots in more than half of the synovial area. A joint with US synovitis was defined as a joint in which any of the 3 US abnormalities was detectable. PDUS was considered positive in the presence of vessel dots on PDUS images only out of growing cartilage and if it was not a bone nutrition vessel. The US examination technique as well as the definitions and scoring of US features were based on published guidelines provided by the OMERACT in adults. Results MSUS revealed the presence of 1 or more alterations of the synovial structures (effusion, hyperplasia or positive PDUS) in 23 out of 100 pts who satisfied the clinical criteria of ID according to Wallace definition (23%). 9 pts (39% out of 23 active pts & 9% out of all 100 pts) have only one joint involved. The other 14 pts (61% out of 23 active pts & 14% out of all 100 pts) presented US activity in more than one joint. 43 of the 4200 examined joints were active at US (1,02%). In 17 of these 43 joints (39%) US revealed joint effusion, hyperplasia and PDUS. In 29 joints (67%) there were only two of these US features. No abnormalities were found in healthy controls. Conclusions Our data confirm the usefulness of US in pediatric joint examination to identify active joints in JIA pts, to set up an appropriate treatment and to define inactive disease in a more accurate way than referring only to Wallace criteria. Further studies are needed to understand if these findings are related to a greater frequency of relapses. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5618

Background In Rheumatic Ultrasonographic evaluation interest has been raised about the use of power Doppler ultrasonography (PDUS) in the assessment of inflammatory changes in the articular and periarticular structures of children.Nevertheless, there are methodological and interpretative problems due to a lack of ultrasound definition of both the normal joint components and their physiological vascularization in the young population. Objectives To perform PDUS examination of the principal enthesises of healthy children, focusing particularly on their vascularization. Methods We enrolled 33 children (age between 2 and 12 years) Children were assessed by an expert pediatric rheumatologist in order to exclude subjects with clinical history or evidence of muscoloskeletal diseases. The same day a rheumatologist, performed a PDUS examination of the enthesises. The following enthesises were scanned: distal quadriceps tendon, distal and proximal patellar ligament, distal Achilles tendon, medial and lateral epicondyle tendons of the elbow. According to the OMERACT the following elements were evaluated: enthesis thickness, structure or calcifications, bone proliferation, erosions.Vascularization at enthesis level was judged as present or absent in three areas: 1) at the outer edge of the enthesis (peripheral vessel), 2) inside the enthesis (intratendinous vessel), 3) inside the epiphyseal cartilage at the insertion of the enthesis (cartilaginous vessel). Results The remaining 31 subjects were 18 girls and 13 boys, average age 8 years (±2.9). 256 enthesises were evaluated: 180 enthesises of the knee, 40 Achilles enthesises, 36 elbow enthesises. In the gray scale no abnormalities in the enthesises, in the cortical bone or epiphyseal cartilage were idientified. 1) The power Doppler examination showed at least a peripheral vessel around the quadriceps enthesis in 43% of the subjects, around the proximal patellar enthesis in 20%, around the distal patellar enthesis in the 10%, around the Achilles enthesis in the 5%, none around the lateral epicondyle enthesis and in the 22% of subjects around the medial epicondyle enthesis of the elbow. The quadriceps and superior patellar peripheral vessels usually go into the middle part of the patella.2) An intratendinous power Doppler signal was found only in the quadriceps enthesises and it was detected in the 23% of the subjects; this vascular signal appeared always in the same area, that was the distal part of the enthesis, near to the superior pole of the patellar cartilage.3) Cartilagineous vessels adjacent to the enthesis were found close to the quadriceps tendon in the 20% of subjects, close to the proximal patellar tendon in the 30% of the cases, close to the distal patellar tendon in the 47% of the children, close to the Achilles tendon in the 10% of the entheses, close to the lateral epicondyle entheses of the elbow in 67% of the subjects and in the 47% of subjects close to the medial epicondyle entheses of the elbow. Conclusions Power Doppler examination of pediatric enthesis in healthy children can show physiological vessels. These vessels are mainly peritendineus or cartilaginous.Intratendineous vascularization is absent in healthy enthesis, except for the distal part of quadriceps tendon and this finding could represent a pitfall if detected within a context of disease Disclosure of Interest None Declared

Background PANDAS is a syndrome characterized by obsessive-compulsive disorder (OCD) and/or tic disorder with symptom exacerbations in children after group A β-hemolytic streptococcal (GAS) infections. No cardiac nor articular involvement is present as in the case of Sydenham Chorea. Antinuclear antibodies and nuclear basal involvement at brain MR may be encountered. Objectives We evaluated the possible misdiagnosed cardiac and articular involvement in 30 children affected by PANDAS and regularly assessed at an out-patient ambulatory in the period from 2007 to 2011. Methods 30 children affected by PANDAS according the Swedo SA diagnostic criteria were evaluated at the out-patient ambulatory of the Rhematologic and Neuropsichiatric departments of Verona’s University Hospital in the period from 2007 to 2011; thorough cardiologic evaluation encompassing ECG and echocardiogram was performed Results mean age of the 30 young patients (M:F 23:7) was 7±3 years; all had sierologic evidence of previous streptococcal infection; ECG was normal in all the cases as well as cardiac echogram with the exception of 2 cases of trivial mitral regurgitation without structural valvular alterations; no patient was affected by perferic arthritis, arthargias nor morning stiffness. Conclusions the absence of cardiac or articular involvement in PANDAS patients, as evidenced in this study, confirms its differential diagnosis with Sydenham Chorea Disclosure of Interest None Declared

Background Receptors for IgG play an important part in immune complex clearance. Several studies have investigated the polymorphism 158V/F of Fc fragment of IgG (FcgR) type IIIa as genetic factor influencing disease course after rituximab (RTX) therapy in several rheumatologic and haematological diseases, with contrasting, unreplicated results. Objectives To investigate the FcgRIIIa 158V/F polymorphism in a large Italian retrospective cohort of patients with rheumatoid arthritis treated with RTX. Methods The study was conducted in 222 unselected RA patients referred to 13 rheumatologic centres in Italy. All patients were treated with RTX (alone or in combination with DMARDs) at standard doses. Response to therapy (DAS28; EULAR criteria) was evaluated at months +4 (data available in 213 cases) and +6 (data available in all cases) after the first RTX infusion. The FcgRIIIa polymorphism was analysed by PCR followed by Sanger’s sequencing. Results Patients with the VV genotype showed the highest rate of response to RTX both at month +4 (good/moderate in 32/37, 86.5% of the VV patients) and at month +6 (good/moderate response in 34/38, 89.5% of the VV patients) while VF and FF patients showed the same response rate either at month +4 (good/moderate in 70/103, 68% VF and in 53/73, 72.6% FF patients; VV versus VF/FF: OR 2.76, 95%CI 1.02-7.47, *p=0.043) and at month +6 (good/moderate in 69/105, 65.7% VF and in 49/75, 65.3% FF patients; VV versus VF/FF: OR 4.47, 95%CI 1.52-13.16, **p=0.0032). Conclusions The VV genotype of the 158V/F FcgRIIIa polymorphism identifies RA patients who demonstrate the highest rate of positive response to RTX. By contrast, no difference was noticed between VF and FF patients. Disclosure of Interest None Declared