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IntroductionSystemic lupus erythematosus (SLE) is characterized by early atherothrombosis. Pulse wave velocity (PWV) is a promising tool for the diagnosis of early vascular remodelling and initial atherosclerotic plaque formation. Our objective was to evaluate PWV and its relationship with coronary atherosclerosis and thrombotic biomarkers in patients with SLE.Material and methodsIn 26 patients with SLE with stable clinical conditions, mean age of 39.1 ±11.7 years and without a history of coronary artery disease, multidetector computed tomography (MDCT)-based coronary calcium scoring (CACS) was performed and PWV measured. Laboratory evaluation included serum levels of anticardiolipin and anti-β2-glycoprotein antibodies (anti-β2-GPI), lupus anticoagulant (LA), D-dimers, thrombin–antithrombin complexes (TAT), and von Willebrand factor (vWF).ResultsMultidetector computed tomography revealed coronary calcifications in 8 (30.8%) patients and the median CACS was 52.4 HU (range 2–843.2). The mean PWV was 9.0 ±3.2 m/s and was higher in patients aged > 50 years (+33.7% vs. 0; +21.4% vs. CACS = 0). In contrast, the duration of the disease, D-dimers, anticardiolipin, and anti-β2-GPI antibodies did not influence PWV. In the group without atherosclerosis (CACS = 0, n =18), patients with vWF ≥ 200 IU/dl had a 19.3% higher PWV compared to the rest.ConclusionsIn patients with SLE, PWV was associated with the presence of coronary atherosclerotic lesions in MDCT. Furthermore, arterial stiffness was higher in patients with markers of endothelial dysfunction and a prothrombotic state, suggesting their contribution to the early stages of arterial remodelling in SLE.

Fever has been recently included in the new 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). Thus, we investigated the possible association of fever with other clinical disease manifestations. Then, we analysed a panel of 30 SNPs to verify their possible contribution to the pathogenesis of this constitutional symptom.In this retrospective study we collected clinical/laboratory features in a SLE cohort, including the occurrence of fever (body temperature37.5°C, excluding infective aetiology). A phenotype-genotype correlation analysis was carried out.We evaluated 167 patients (M/F 12/155, median age at the disease diagnosis 30 years, IQR 17; median disease duration 240 months, IQR 156). Seventy patients (41.9%) reported fever, significantly associated with: serositis and haematological manifestations (p=0.02 and p=0.00001, respectively). A significant association between fever and leukopenia (p=0.003), haemolytic anaemia (p=0.04), and thrombocytopenia (p=0.04) was observed. In addition, significantly higher median SLICC Damage Index (SDI) values were observed in patients with fever in comparison with those without [2 (IQR 3) vs. 1 (IQR 2); p=0.005]. The genotype/phenotype analysis showed an association between fever and the rs13361189 of Immunity Related GTPase M (IRGM) gene (p=0.003; OR 3.89, CI 1.16-13.03), confirmed also in multivariate logistic regression analysis (p=0.028, B=1.39).The association between IRGM rs13361189 polymorphism and the occurrence of inflammatory fever, could provide new insights into the role of genetic background in the pathogenesis of this SLE-related feature.

Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients. © 2020

Baricitinib is a Janus-kinase (JAK) 1/2 inhibitor, approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). We report the first real-life experience with baricitinib in a monocentric cohort of unselected RA patients.We enrolled consecutive RA patients starting baricitinib. At baseline and after 4, 12, 24 and 48 weeks we assessed the disease activity by composite indices (SDAI, CDAI and DAS28CRP) and ultrasonography, and we recorded any adverse events. The primary endpoint was the percentage of patients achieving SDAI remission at week 4.We enrolled 59 patients [(F:M = 50:9, median age 58.1 years (IQR 12.8), median disease duration 144 (IQR 150) months] treated with baricitinib in combination with a csDMARD (52.5%) or monotherapy (47.5%) for a median follow-up of 24 weeks (IQR 36). The 12-month drug retention rate was 74%. At weeks 4, 12, 24 and 48 we observed a significant reduction of DAS28, CDAI and SDAI, global health and pain (p0.001 for all). After 4 weeks of treatment, 12% of patients achieved SDAI remission. Concomitant csDMARDs, previous biological DMARDs, gender, seropositivity and BMI did not affect the efficacy of baricitinib. Baricitinib allowed a significant reduction in prednisone dose after 12 and 24 weeks and a rapid and sustained ultrasound improvement. No serious adverse events, serious infections or cardiovascular events were recorded.Our study confirms the efficacy and safety profile and rapid onset of the effect of baricitinib in RA patients in a real-life setting.

COVID-19 features include disseminated intravascular coagulation and thrombotic microangiopathy indicating a hypercoagulable state. We aimed to investigate antiphospholipid antibodies (aPL) prevalence and clinical relationships in a large cohort of COVID-19 patients.We analysed the prevalence and titres of serum aPL in 122 patients with COVID-19 and 157 with primary antiphospholipid syndrome (PAPS) and 91 with other autoimmune rheumatic diseases (oARD) for comparison. IgG/IgM anticardiolipin (aCL) and IgG/IgM anti-beta2glycoprotein I (β2GPI) were assayed using homemade ELISA, IgA aCL and anti-β2GPI by commercial ELISA kits and lupus anticoagulant (LAC) by multiple coagulation tests following updated international guidelines.Prevalence of IgG and IgM aCL and of IgG and IgM anti-β2GPI across COVID-19 patients were 13.4%, 2.7%, 6.3% and 7.1%, being significantly lower than in PAPS (p0.0001 for all). Frequency of IgG aCL and IgM anti-β2GPI was comparable to oARD (13.4% vs. 13.2% and 7.1% vs. 11%, respectively), while IgG anti-β2GPI and IgM aCL were lower (p0.01). IgA aCL and IgA anti-β2GPI were retrieved in 1.7% and 3.3% of COVID-19 patients, respectively. Positive LAC was observed in 22.2% COVID-19 vs. 54.1% of PAPS (p0.0001) and 14.6% of oARD (p=0.21). Venous or arterial thromboses occurred in 18/46 (39.1%) COVID-19 patients and were not associated with positive aPL (p=0.09).Thrombosis is a frequent manifestation during COVID-19 infection. However, prevalence and titres of aPL antibodies or LAC were neither consistently increased nor associated with thrombosis when measured at a single timepoint, therefore not representing a suitable screening tool in the acute stage of disease.

Cyclophosphamide treatment has been associated with ovarian function impairment. Co-treatment with gonadotropin-releasing hormone-analogue (GnRH-a) seems to be able to prevent this complication. However, even though data are available on neoplastic patients, limited data have been published on systemic lupus erythematosus (SLE) women cohorts.To evaluate GnRH-a efficacy on ovarian function preservation in SLE women receiving cyclophosphamide treatment.The authors performed a retrospective study including SLE women requiring cyclophosphamide treatment and compared those treated with and without GnRH-a (case and controls, respectively). All patients were evaluated before cyclophosphamide treatment and every 3 months in the following years. Ovarian function was evaluated using hormonal profiles.The study comprised 33 SLE cyclophosphamide-treated women: 18 co-treated with triptorelin and 15 controls. The mean follow-up was 8.1 ± 5.1 years (range 4-11). Premature ovarian failure (POF) prevalence was significantly lower in SLE women treated by cyclophosphamide plus triptorelin compared to controls (11.1% vs. 33.3%, P = 0.0002). The occurrence of POF was significantly associated with higher age at the time of cyclophosphamide treatment (P = 0.008). Only patients in the GnRH-a treated group had successful pregnancies.The study provides information about the efficacy of co-treatment with GnRH-a in SLE women receiving cyclophosphamide, as demonstrated by the lower POF incidence compared to untreated subjects, based on long-term follow-up. These results reinforce the use of GnRH-a for fertility preservation in premenopausal SLE patients treated by cyclophosphamide.

Immunological parameters exert a relevant diagnostic and prognostic role in primary Sjögren's syndrome (pSS) and may identify specific disease phenotypes. Among disease-associated immunological features, anti-La/SSB are rarely found without concomitant anti-Ro/SSA and their clinical significance in patients with pSS has been poorly investigated. Thus, we aimed to characterise the value of anti-La/SSB analysing clinical and serologic features of a wide cohort of pSS patients with both circulating anti-Ro/SSA and positive salivary gland biopsy (SGB).Clinical and serological data of 600 pSS patients with both anti-Ro/SSA and SGB positivity and categorised according to anti-La/SSB status were retrospectively analysed. Comparisons between patients with and without circulating anti-La/SSB were performed.Among the whole cohort, 319 (53%) of patients were anti-La/SSB negative and 281 (47%) were anti-La/SSB positive. Anti-La/SSB positive patients were younger at disease diagnosis and had a longer disease duration. Moreover, anti-La/SSB positive patients had a higher prevalence of hypergammaglobulinaemia and circulating rheumatoid factor and of lymphoproliferative disorders in comparison to seronegative group. At multivariate analysis, hypergammaglobulinaemia (OR=1,7; 95% CI 1.17, 2.43), rheumatoid factor (OR=2.3; 95% CI 1.6, 3.3) and lymphoma (OR=2.6; 95% CI 1.12, 5.96) were identified as independent variables significantly associated with anti-La/SSB positivity.In patients with pSS and concomitant anti-Ro/SSA and SGB positivity, the presence of anti-La/SSB may help in identifying a disease subset with distinct prognostic features, especially in terms of higher risk of lymphoproliferative complications.

Objectives: Salivary gland ultrasonography (SGUS) is increasingly applied for the management of primary Sjögren's syndrome (pSS). This study aims to: (i) compare the reliability between two SGUS scores; (ii) test the reliability among sonographers with different levels of experience. Methods: In the reliability exercise, two four-grade semi-quantitative SGUS scoring systems, namely De Vita et al. and OMERACT, were tested. The sonographers involved in work-package 7 of the HarmonicSS project from nine countries in Europe were invited to participate. Different levels of sonographers were identified on the basis of their SGUS experience and of the knowledge of the tested scores. A dedicated atlas was used as support for SGUS scoring. Results: Twenty sonographers participated in the two rounds of the reliability exercise. The intra-rater reliability for both scores was almost perfect, with a Light's kappa of 0.86 for the De Vita et al. score and 0.87 for the OMERACT score. The inter-rater reliability for the De Vita et al. and the OMERACT score was substantial with Light's Kappa of 0.75 and 0.77, respectively. Furthermore, no significant difference was noticed among sonographers with different levels of experience. Conclusion: The two tested SGUS scores are reliable for the evaluation of major salivary glands in pSS, and even less-expert sonographers could be reliable if adequately instructed. © Copyright © 2020 Zabotti, Zandonella Callegher, Tullio, Vukicevic, Hocevar, Milic, Cafaro, Carotti, Delli, De Lucia, Ernst, Ferro, Gattamelata, Germanò, Giovannini, Hammenfors, Jonsson, Jousse-Joulin, Macchioni, Parisi, Perricone, Stradner, Filipovic, Tzioufas, Valent and De Vita.

Kidney biopsy is the gold standard for the diagnosis of lupus nephritis (LN). Conventional biomarkers of disease activity or renal function, such as complement levels, anti-dsDNA, serum creatinine, urinary sediment and proteinuria, do not have a sensitive diagnostic and prognostic value, therefore new biomarkers are needed to help predict or monitor LN. Osteopontin (OPN) is a pro-inflammatory molecule detectable in serum and renal tissue. The aim of this study was to evaluate OPN as a biomarker of renal involvement in patients with systemic lupus erythematosus (SLE) and correlate its levels with disease activity and laboratory features.OPN was measured in the serum and urine of SLE patients with active LN (n=14), LN in remission (n=20), SLE without kidney involvement (n=22) and age- and sex-matched healthy controls (HC, n=20).OPN levels were significantly higher in urine than in serum in both groups of patients and controls (p0.001). Serum OPN levels were higher in the LN patients than in HC and in SLE patients without renal involvement (p0.0001 and 0.0032, respectively), regardless of the phase of renal activity. SLE patients without renal involvement and controls showed similar serum levels. We detected a direct correlation between low complement levels and OPN serum levels in patients with LN (p=0.014; R=0.438). Moreover, a higher percentage of patients with LN, compared to SLE without LN and HC, showed abnormal serum OPN.Our data suggest that serum OPN could be considered a biomarker of renal involvement, without differentiating between active and remission LN.

The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP).The value of a new simpler procedure to derive international normalized ratio (INR), the PT/INR Line, based on only five European Concerted Action on Anticoagulation (ECAA) calibrant plasmas certified by experienced centres has been assessed in two independent exercises using a range of commercial thromboplastins and coagulometers. INRs were compared with manual certified values with thromboplastin IRP from expert centres and in the second study also with INRs from local ISI calibrations.In the first study with the PT/INR Line, 8.7% deviation from certified INRs was reduced to 1.1% with human reagents, and from 7.0% to 2.6% with rabbit reagents. In the second study, deviation was reduced from 11.2% to 0.4% with human reagents by both local ISI calibration and the PT/INR Line. With rabbit reagents, 10.4% deviation was reduced to 1.1% with both procedures; 4.9% deviation was reduced to 0.5% with bovine/combined reagents with local ISI calibrations and to 2.9% with the PT/INR Line. Mean INR dispersion was reduced with all thromboplastins and automated systems using the PT/INR Line.The procedure using the PT/INR Line provides reliable INR derivation without the need for WHO ISI calibration across the range of locally used commercial thromboplastins and automated PT systems included in two independent international studies.? 2010 International Society on Thrombosis and Haemostasis.

Introduction: B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in autoimmune diseases. The significance of soluble CD72 (sCD72) has not been elucidated. Methods: Soluble CD72 was analyzed in the serum of 159 SLE patients, 40 rheumatoid arthritis (RA) patients, and 100 healthy individuals. Correlations between sCD72 and SLE disease activity (SLEDAI) were assessed. Results: Soluble CD72 was found increased in SLE patients, when compared to both RA patients and healthy individuals (20.2 ± 1.2 ng/ml; 10.6 ± 4.6 ng/ml and 7.2 ± 3.3 ng/ml; p < 0.001). Soluble CD72 level was significantly higher in SLE patients with renal involvement than in patients without (31.8 ± 2.3 ng/ml vs 13.9 ± 0.9 ng/ml; p < 0.001) and also with the presence of auto-antibodies. Conclusion: Soluble CD72 is significantly increased in SLE patients mainly in those with renal involvement. Increased sCD72 may become a potential biomarker for renal involvement in SLE. © 2015 .

Sarcoidosis is a chronic multisystem disease with variable course resulting from the interaction between environmental factors and the immune system of individuals genetically predisposed. The evidence linking sarcoidosis with environmental triggers such as metals is increasing. We describe the case of a 44 year old female with a history. of smoking since age 30 and previous mercury dental filling who presented at physical examination with numerous subcutaneous nodules. Laboratory data showed accelerated erythrocyte sedimentation rate and high titer of anti-U1 ribonucleoprotein antibodies (U1 RNP). Skin biopsy and chest X-ray suggested the diagnosis of sarcoidosis. In this report we illustrate the different causes involved in the onset of sarcoidosis.

Objective:The objective of this study was to draw up a set of recommendations for the format and content of the musculoskeletal ultrasonography (MSUS) report in rheumatology. METHODS: A panel of rheumatologists, members of the MSUS Study Group of the Italian Society of Rheumatology, met in order to identify the main discrepancies in the MSUS report. A set of 15 recommendations was then defined, aimed at resolving the main discrepancies. They consisted of information about the motivations for the MSUS examination, the equipment, the US modalities and scanning technique, a list of the examined structures and findings, the scoring/grading systems, the number of images and main findings to include and conclusions. Subsequently a Delphi-based procedure was started in order to obtain agreement on a core set of recommendations. Consensus for each recommendation was considered achieved when the percentage of agreement was >75%. RESULTS: Three complete rounds were performed. The response rate was 85.2% for the first round, 78.3% for the second and 88.9% for the third. Finally, consensus was obtained for 14 of 15 statements. These 14 statements represent the recommendations of the group for the format and content of the report and documentation in MSUS in rheumatology. CONCLUSION: To the best of our knowledge, our group has produced the first recommendations for the format and content of the report and documentation in MSUS in rheumatology. The report is an integral part of the MSUS examination and its use in a homogeneous form can help in the correct interpretation of the findings.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem involvement due to immune dysregulation. Neuropsychiatric systemic lupus erythematosus (NPSLE) includes neurological syndromes involving the central, peripheral and autonomic nervous system, as well as psychiatric syndromes observed in patients with SLE in which other causes have been excluded. The pathogenesis of NPSLE has been attributed to many different mechanisms. In particular, autoantibody-mediated vasculopathy seems to play a major role in the pathogenesis of the clinical features. Several autoantibody specificities have been reported in the serum and cerebrospinal fluid of NPSLE patients. Recently, we demonstrated an association between serum antiendothelial antibodies (AECA) and psychosis or depression in SLE patients, strengthening the notion of a possible role of this class of autoantibodies in the pathogenesis of the disease. The study of these autoantibodies could be a useful diagnostic and prognostic tool in patients with NPSLE.

Dear Sir, Treatment of haemophilia is costly, and it must be carefully monitored by physicians and health authorities, so as to improve the planning of the supply of factor concentrates obtained from the fractionation of human plasma or by recombinant technology. Therapy with coagulation factors can be used either prophylactically to prevent bleeding, which entails multiple weekly infusions, or on-demand, through infusion of the amount of factors determined by the severity of the disease and patient’s weight, to stop ongoing bleeding. According to a recent study, factor VIII (FVIII) consumption among persons with haemophilia A (HA) has increased in countries with high-income economies (Stonebraker et al., 2010). In Italy, haemophiliacs and other persons with congenital coagulation disorders are monitored by the National Registry of Congenital Coagulopathies (NRCC) established at the Istituto Superi=

von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting both males and females. It arises from quantitative or qualitative defects of von Willebrand factor (VWF) and causes bleeding of mucous membranes and soft tissues. The aim of treatment is to correct the dual defect of haemostasis caused by the abnormal/reduced VWF and the concomitant deficiency of factor VIII (FVIII).This document contains evidence-based recommendations for the management of VWD compiled by AICE (the Italian Association of Haemophilia Centres). All the evidence supporting these recommendations are based on non-randomised comparative studies or case series, because randomised controlled clinical trials or meta-analyses are not available for this disease.Desmopressin (DDAVP) is the treatment of choice for patients with type 1 VWD with FVIII and VWF levels of 10 U/dL or more, while VWF/FVIII concentrates are indicated for those who are unresponsive or insufficiently responsive to DDAVP (severe type 1, type 2 and 3 VWD). VWF concentrates devoid of FVIII, not yet licensed in Italy, may be considered for short-term prophylaxis in elective surgery or for long-term secondary prophylaxis.

National haemophilia registries are powerful instruments to support health care and research. A national registry was established in Italy by the Ministry of Health until 1999. Since 2003 the Italian Association of Haemophilia Centres (AICE) started a new programme aiming at building up the Italian Registry of Haemophilia and Allied Disorders. The AICE identified an expert panel to steer the registry. A computer software to assist patient management was developed and all the AICE-affiliated haemophilia treatment centres (HTC) were prompted to adopt it. Twice a year a predefined set of anonymized data is centralized and merged into a national database. Duplicated entries are managed through a confidentiality sparing mechanism. The database covers sociodemographic, clinical, laboratory and treatment data. A subset of data are shared with the Ministry of Health (Istituto Superiore di Sanita,ISS).Overall, data were collected six times by 43 of 49 HTC; 41 centres updated their patients' records up to December 2006. The database contains 6632 unique records, 442 of them referring to dead patients. Database growth and missing data clearance showed a constantly positive trend over time. The database has collected records of the following alive patients - haemophilia A: 1364 severe, 398 moderate and 935 mild; haemophilia B: 231 severe, 138 moderate and 204 mild; von Willebrand's disease: 1208 type 1, 346 type 2 and 96 type 3. Inhibitor patients were 296 (of which 194 high responders and 65 low responders).The Italian registry run by AICE adds to the list of the available national haemophilia registries and is intended to establish treatment guidelines and foster research projects in Italy.

To provide a survey of disease activity in patients treated with standard care in Italian clinical practice.This was an observational prospective cohort study in patients with early, aggressive rheumatoid arthritis (RA; duration ≤2 years but ≥6 weeks; DAS283.2) naïve to anti-tumour necrosis factor (TNF) therapy who were treated with disease-modifying anti-rheumatic drugs (DMARDs) and/or biologics according to standard practice at 15 Italian ARPA (Artrite Reumatoide Precoce Aggressiva) centres. Patients were evaluated at baseline and after 6, 12 and 24 months. The primary endpoint was the proportion of patients achieving remission, as defined by disease activity score in 28 joints (DAS28)2.6, after 1 year.Among the 152 patients enrolled, 92 were evaluable after 1 year and 77 after 2 years for DAS28. At baseline, patients had a mean DAS28 of 6.1±1.0. At 12 months, 62.6% of patients were treated with DMARDs (in monotherapy or in combination), and 37.4% with anti-TNFs (in monotherapy or in association with DMARDs). At 24 months, 35.1% were receiving anti-TNF therapy. The rate of DAS28 remission rates at 12 months and 24 months were 28.3% (95% confidence interval [CI] 19.1-37.5) and 41.6% (95% confidence interval [CI] 30.6-52.6), respectively.The remission rate was lower at 12 months compared with previous large randomised clinical trials for early, aggressive RA, but significantly improved at 24 months. These results suggest that patients in real-world clinical settings in Italy may experience a delay in receiving the best possible care.