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To detail the unmet clinical and scientific needs in the field of rheumatology. After a 2-year hiatus due to the SARS-CoV-2 pandemic, the 22nd annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. Breakout sessions were convened with experts in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and connective tissue diseases (CTDs). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research, as well as highlight recent progress in meeting formerly identified unmet needs. Clinical trial design innovation was emphasised across all disease states. Within RA, developing therapies and trials for refractory disease patients remained among the most important identified unmet needs and within lupus and spondyloarthritis the need to account for disease endotypes was highlighted. The RA group also identified the need to better understand the natural history of RA, pre-RA states and the need ultimately for precision medicine. In CTD generally, experts focused on the need to better identify molecular, cellular and clinical signals of early and undifferentiated disease in order to identify novel drug targets. There remains a strong need to develop therapies and therapeutic strategies for those with treatment-refractory disease. Increasingly it is clear that we need to better understand the natural history of these diseases, including their ‘predisease’ states, and identify molecular signatures, including at a tissue level, which can facilitate disease diagnosis and treatment. As these unmet needs in the field of rheumatic diseases have been identified based on consensus of expert clinicians and scientists in the field, this document may serve individual researchers, institutions and industry to help prioritise their scientific activities.

ObjectiveThe aim of this work is to explore patient’ unmet needs of rare and complex rheumatic tissue diseases (rCTDs) patients during pregnancy and its planning by means of the narrative-based medicine (NBM) approach.MethodsA panel of nine rCTDs patients’ representatives was identified to codesign a survey aimed at collecting the stories of rCTD patients who had one or more pregnancies/miscarriages. The results of the survey and the stories collected were analysed and discussed with a panel of patients’ representatives to identify unmet needs, challenges and possible strategies to improve the care of rCTD patients.Results129 replies were collected, and 112 stories were analysed. Several unmet needs in the management of pregnancy in rCTDs were identified, such as fragmentation of care among different centres, lack of education and awareness on rCTD pregnancies among midwifes, obstetricians and gynaecologists. The lack of receiving appropriate information and education on rCTDs pregnancy was also highlighted by patients and their families. The need for a holistic approach and the availability specialised pregnancy clinics with a multidisciplinary organisation as well as the provision of psychological support during all the phases around pregnancy was considered also a priority.ConclusionThe adoption of the NBM approach enabled a direct identification of unmet needs, and a list of possible actions was elaborated to improve the care of rCTD patients and their families in future initiatives.

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Here we describe the case of a 38-year-old man with a history of ischemic transient attacks and strokes from the age of 9 years, livedo reticularis, asymmetrical sensorimotor neuropathy, optic neuritis, testicular ischemia, digital ulcers, ulcerative colitis, and diastolic hypertension. Disease course was characterized by severe disease bouts treated with high-dose intravenous (IV) glucocorticoid (GC) pulse therapy, short periods of paucisymptomatic disease, and inability to taper GCs despite the use of traditional oral and IV immunosuppressants, interferon, and plasmapheresis.

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy classically presenting with sicca symptoms. Nonetheless, disease onset with extraglandular manifestations, including interstitial lung disease (ILD), is increasingly reported. However, studies investigating pSS patients presenting with ILD (pSS-ILD) are limited.Aim of this study was to better characterise the phenotype of pSS patients presenting with ILD in comparison to pSS patients with classicsicca-onset. We especially investigated whether the two groups differed in glandular involvement comparing functional, imaging andhistologic findings, as well as patient reported outcome (PRO).Consecutive newly diagnosed pSS patients, all fulfilling the ACR/EULAR 2016 criteria, were included in this cross-sectional study from September 2016 to October 2021. Presence of ILD at pSS diagnosis was defined based on clinical findings, imaging assessment and pulmonary function tests (PFT). In addition to functional tests, a minor salivary gland biopsy was performed in all cases, recording number of foci, focus score (FS) and GC-like structures. Salivary glands ultrasonography (SGUS) was graded using the OMERACT semiquantitative scoring system (0-3) based on parenchyma inhomogeneity. PRO including ESSPRI, OHIP and OSSDI were collected.Extraglandular clinical features and biological abnormalities included in the ESSDAI were recorded. Data were expressed as mean±SD for continuous variables and as absolute frequencies and percentages for categorical variables. Chi-Square test and Mann-Whitney U-test and ANOVA were performed for comparisons of categorical variables and continuous variables, respectively.We included 178 newly diagnosed pSS patients (F:M=158:20). ILD was the first pSS manifestation in 11 (6%) cases, 8 F and 3 M, with a median time from ILD onset to pSS diagnosis of 2 years (25-75 IQ 1-4.5). Of the 11 pSS-ILD patients, HRCT pattern was defined as NSIP in 4, UIP in 4, NSIP+OP in 2 and LIP in 1 patient. Dyspnoea on exertion or chronic cough were reported by 7/11 (63.6%) patients.In comparison to sicca-onset patients, pSS-ILD patients presented an older age at diagnosis (55±13 vs. 70±7, p= 0.001) and a higher ESSDAI (3.9±4.7 vs. 12.3±4.3, p=0.001), driven by the pulmonary domain. Regarding glandular involvement, pSS-ILD patients reported milder xeropthalmia (VAS 5.8±3.1 vs. 2.8±3.5, p=0.002) and significative lower scores in OSDI (35.6±24.9 vs. 15.3±22.9, p=0.04) and OHIP (4.8±4.4 vs. 1.4±3.8, p=0.04), despite no significant differences observed between the two groups in ocular tests and unstimulated salivary flow rate. With respect to histology, no significant differences were found in number of foci, FS and GC-like structures. We observed a significantly different distribution of the SGUS OMERACT score in the two groups: none of pSS-ILD patients presented a SGUS OMERACT score ≥2 in the submandibular glands (SG), in contrast to 41/132 (31.1%) of the patients in the classical sicca-onset group (p=0.03). Finally, no significant differences were observed between the two groups with respect to non-pulmonary extraglandular manifestations, serologic features and other biological parameters.ILD-onset pSS patients represent an atypical phenotypic subset, with less pronounced sialadenitis structural changes in salivary glands, and with sicca symptoms probably overshadowed by the respiratory disease.

The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.

ObjectiveSystemic sclerosis (SSc) is burdened by Raynaud phenomenon (RP) and digital ulcers (DUs), and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate the clinical and instrumental efficacy of selexipag in SSc digital vasculopathy.MethodsPatients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag. RP- and DU-related clinical outcomes were evaluated, and digital perfusion was assessed by laser speckle contrast analysis (LASCA), all at baseline and after 3 months.ResultsSelexipag was administered to 9 patients with SSc (66.6% female, mean age 52.3 [SD 16.6] yrs). One patient had to stop the drug because of adverse effects. After 3 months of selexipag administration, there was a significant reduction in RP daily episodes (P= 0.01) and RP mean duration (P= 0.04). The number of DUs decreased from 10 to 4 without reaching statistical significance. A significant improvement in mean perfusion of the fingers (P= 0.02) was observed with LASCA.ConclusionSelexipag showed good potential for the treatment of SSc digital vasculopathy. Our results are certainly preliminary, yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc digital vasculopathy are needed.

ObjectiveTo use bioelectrical impedance vector analysis (BIVA) in a cohort of patients with systemic sclerosis (SSc) in order to assess their nutritional status in comparison to other groups of patients and to find any correlation with clinical characteristics and outcome of the disease.MethodsWe retrospectively collected data from 50 SSc patients who underwent BIVA for clinical suspicion of malnutrition and compared them with patients affected by other chronic autoimmune rheumatic diseases (OCAD, n = 27) and those who were only symptomatic of malnutrition but without autoimmune features (n = 15), and with 50 healthy controls (HC).ResultsPatients with SSc presented significantly lower values of phase angle (PhA), basal metabolic rate (BMR), and body cellular mass (BCM), and an increase in extracellular water (ECW; P < 0.01 for all) than HC; instead, there were no significant differences for BMI. No significant differences were found between SSc and OCAD. Among patients with SSc, age directly correlated with ECW (ρ = 0.342, P = 0.015) and inversely with PhA (ρ = –0.366, P = 0.009). Female sex, anemia, hypoalbuminemia, reflux, and early satiety/abdominal distension associated with relevant alterations in BIVA results. BIVA variables were significantly different when cardiopulmonary and microvascular involvement was present. Four patients died during the study: they had significantly (P ≤ 0.01) lower PhA, BMR, and BCM, with an increased ECW.ConclusionBIVA, unlike BMI, allowed an accurate characterization of SSc patients at risk of malnutrition, correlating with serological malnutrition markers, with SSc-specific organ manifestations (cardiopulmonary involvement and microvascular damage), and with mortality. BIVA variables might represent a surrogate marker of damage accrual that leads to malnutrition, thus playing a leading role in the prognostic stratification of SSc patients.

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients. It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as “unmet needs”, such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.

© Copyright Clinical and Experimental Rheumatology 2022., Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

ObjectiveA subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP).MethodsPatients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDNResultsThe GULP study included 127 patients with SLE; 73 (57.5%) tapered and maintained PDN ConclusionTapering PDN

ObjectivesTo describe the safety of vaccines against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal disease (I-RMD).MethodsPhysician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5 February 2021 to 27 July 2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively.ResultsThe study included 5121 participants from 30 countries, 90% with I-RMDs (n=4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n=517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying antirheumatic drugs (DMARDs), 42% biological DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD).ConclusionThe safety profiles of SARS-CoV-2 vaccines in patients with I-RMD was reassuring and comparable with patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients.

ObjectiveTo map existing organizational care pathways in clinical centers of expertise that care for pregnant women affected by rare and complex connective tissue diseases (rcCTDs).MethodsAn international working group composed of experts in the field of pregnancy in rcCTDs co-designed a survey focused on organizational aspects related to the patient's pathway before, during, and after pregnancy. The survey was distributed to subject experts through referral sampling.ResultsAnswers were collected from 69 centers in 21 countries. Patients with systemic lupus erythematosus and/or antiphospholipid syndrome were followed by more than 90% of centers, whereas those with disorders such as IgG4-related diseases were rarely covered. In the majority of centers, a multidisciplinary team was involved, including an obstetrician/gynecologist in 91.3% of cases and other healthcare professionals less frequently. Respondents indicated that 96% of the centers provided routine pre-pregnancy care, whereas the number of patient visits during pregnancy varied across centers. A formalized care pathway was described in 49.2% of centers, and 20.3% of centers had a predefined protocol for the monitoring of pregnant patients. Access to therapies during pregnancy also was heterogeneous among different centers.ConclusionIn international referral centers, a high level of care is provided to patients with rcCTDs before, during, and after pregnancy. No significant discrepancies were found between European and non-European countries. However, this work highlights a potential benefit to streamlining the care approaches across countries to optimize pregnancy and perinatal outcomes among patients with rcCTDs.

© Copyright Clinical and Experimental Rheumatology 2022, Objectives: The purpose of this study was to review the frequency and clinical presentation of the rarest clinical manifestations of systemic lupus erythematosus (SLE). Methods: A list of 6 rare SLE manifestations were defined: gastrointestinal, liver, pulmonary, cardiac, ocular and neurological manifestations. Each topic was assigned to a pair of authors to perform a literature search and article review. Results: In total, 149 articles were included in the literature review: 37 for gastrointestinal manifestations, 6 for liver manifestations, 27 for pulmonary manifestations, 50 for cardiac manifestations, 16 for ocular manifestations, 13 for neurological manifestations. Gastrointestinal disorders included several clinical presentations with variable frequency (from 0.5% to 10.7% of the cases); liver involvement included lupus-related hepatitis (9.3%) and autoimmune hepatitis (2.3%). The rarest pulmonary manifestations identified were shrinking lung syndrome, described in 1.5% of patients, while interstitial lung disease and lupus pneumonia were reported in 4% and 3% of patients respectively. Myocarditis and pulmonary hypertension were also rarely described in SLE patients although ranging from 0.4-16% and 1-14% respectively, depending on the methodology used for its identification. Ocular manifestations in SLE included some rare manifestations (reported in less than 5% of patients) and lupus retinopathy that is described in 1.2-28.8% of patients depending on methods of ascertainment. Aseptic meningitis and chorea were also confirmed as very rare manifestations being reported in less than 1% and in 0.3-2.4% of cases respectively. Conclusions: The results of this literature review provide the basis for a better understanding of some less-known manifestations of SLE and for stressing the need for a higher awareness in diagnostic and therapeutic protocols regarding these rare disease aspects.

Funder: Lupus Foundation of America, Inc, Objective: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. Methods: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966���October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with

ObjectiveTo achieve consensus on a definition of remission in SLE (DORIS).BackgroundRemission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation.MethodsSeveral systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on.ResultsBased on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator’s Global Assessment ConclusionThe 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.

Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia Conclusions Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

BackgroundQuality of care is receiving increased attention in systemic lupus erythematosus (SLE). We developed quality indicators (QIs) for SLE based on the 2019 update of European League Against Rheumatism recommendations.MethodsA total of 44 candidate QIs corresponding to diagnosis, monitoring and treatment, were independently rated for validity and feasibility by 12 experts and analysed by a modified Research and Development Corporation/University of California Los Angeles model. Adherence to the final set of QIs and correlation with disease outcomes (flares, hospitalisations and organ damage) was tested in a cohort of 220 SLE patients with a median monitoring of 2 years (IQR 2–4).ResultsThe panel selected a total of 18 QIs as valid and feasible. On average, SLE patients received 54% (95% CI 52.3% to 56.2%) of recommended care, with adherence ranging from 44.7% (95% CI 40.8% to 48.6%) for diagnosis-related QIs to 84.3% (95% CI 80.6% to 87.5%) for treatment-related QIs. Sustained remission or low disease activity were achieved in 26.8% (95% CI 21.1% to 33.2%). Tapering of prednisone dose to less than 7.5 mg/day was achieved in 93.6% (95% CI 88.2% to 97.0%) while 73.5% (95% CI 66.6% to 79.6%) received the recommended hydroxychloroquine dose. Higher adherence to monitoring-related QIs was associated with reduced risk for a composite adverse outcome (flare, hospitalisation or damage accrual) during the last year of observation (OR 0.97 per 1% adherence rate, 95% CI 0.96 to 0.99).ConclusionWe developed QIs for assessing and improving the care of SLE patients. Initial real-life data suggest face validity, but a variable degree of adherence and a need for further improvement.

Objectives: Intravenous iloprost (ILO) has widely demonstrated its effectiveness and safety in systemic sclerosis (SSc) patients. Unfortunately, there is no clear consent about dosage, duration, frequency, and infusion modality. The aim of this study was to compare two different therapeutic schemes in the same cohort of consecutive SSc subjects, evaluating differences in terms of effectiveness [digital ulcer (DU) outcome], safety, and direct healthcare costs. Method: This was a retrospective observational study of 47 patients classified with SSc treated with intravenous ILO for severe Raynaud’s phenomenon and/or DUs. Two regimens were compared: a continuous inpatient scheme and a daily outpatient scheme. Demographics and clinical data, concomitant therapies, adverse events, and data on resource use and costs were collected. Results: The number of DUs rose slightly with the switch from the continuous to the daily scheme (0.61 ± 1.2 vs 1.1 ± 1.7). Moreover, in the daily scheme there was an increase in the number of therapeutic cycles (2.4 ± 0.7 vs 4.71 ± 1.4, p Conclusion: Treatment with a daily scheme of ILO is characterized by worse tolerability and a higher dropout rate compared to a low-flow regimen, with similar costs. We suggest that a low-flow continuous therapeutic scheme is preferable in SSc patients.

Introduction The aim of this study was to investigate the incidence and clinical presentation of SARS-CoV-2 infections in a Systemic Lupus Erythematosus (SLE) cohort; to assess correlations with disease characteristics and rheumatic therapy; and to evaluate the occurrence of treatment discontinuation and its impact on disease activity. Materials and methods SLE patients monitored by a single Italian centre were interviewed between February and July 2020. Patients were considered to be positive for SARS-CoV-2 infections in case of 1) positive nasopharyngeal swab; 2) positive serology associated with COVID19 suggesting symptoms. The following data were also recorded: clinical symptoms, adoption of social distancing measures, disease activity and treatment discontinuation. Results 332 patients were enrolled in the study. Six patients (1.8%) tested positive for SARS-CoV-2 infection, with the incidence being significantly higher in the subgroup of patients treated with biological Disease-Modifying Anti-Rheumatic Drugs (p = 0.005), while no difference was observed for other therapies, age at enrollment, disease duration, type of cumulative organ involvement or adoption of social isolation. The course of the disease was mild. Thirty-six patients (11.1%) discontinued at least part of their therapy during this time period, and 27 (8.1%) cases of disease flare were recorded. Correlation between flare and discontinuation of therapy was statistically significant (p Conclusion Treatment discontinuation seems to be an important cause of disease flare. Our findings suggest that abrupt drug withdrawal should be avoided or evaluated with caution on the basis of individual infection risk and comorbidities.

Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous clinical manifestations that can potentially affect every organ and system. SLE is usually identified on the basis of clinical or serological manifestations; however, some individuals can present with signs and symptoms that are consistent with SLE but are not sufficient for a definite diagnosis. Disease in these individuals can either progress over time to definite SLE or remain stable, in which case their disease is often described as intermediate, possible or probable SLE. Alternatively, such individuals might have undifferentiated connective tissue disease (UCTD). Being able to differentiate between those with stable UCTD and those with SLE at an early stage is important to avoid irreversible target-organ damage from occurring. This Review provides insight into existing and evolving perceptions of the early stages of SLE, including clinical and mechanistic considerations, as well as potential paths towards early identification and intervention. Further research into the earliest phases of SLE will be important for the development of targeted diagnostic approaches and biomarkers for the identification of individuals with early disease who are likely to progress to definite SLE. Differentiating between the early stages of systemic lupus erythematosus (SLE) and undifferentiated connective tissue disease (UCTD) can be challenging. In this Review, the authors summarize current knowledge on UCTD and early-stage SLE and discuss clinical approaches to diagnosing these conditions.

ObjectivesIn patients with systemic autoimmune rheumatic disorders (SARDs), vaccination with SARS-CoV-2 mRNA vaccines has been proposed. The aim of this study is to evaluate the immune response elicited by vaccination with mRNA vaccine, testing IgM, IgA and IgG antibodies to SARS-CoV-2 receptor-binding domain (RBD) and measuring neutralising antibodies.MethodsIgG, IgM and IgA anti-RBD antibodies were measured in 101 patients with SARDs. Antibodies inhibiting the interaction between RBD and ACE2 were evaluated. Antibody avidity was tested in a chaotropic ELISA using urea. Twenty-one healthcare workers vaccinated with mRNA vaccine served as control group.ResultsAnti-RBD IgG and IgA were produced after the first dose (69% and 64% of the patients) and after the boost (93% and 83%). Antibodies inhibiting the interaction of RBD with ACE2 were detectable in 40% of the patients after the first dose and 87% after boost, compared with 100% in healthy controls (pConclusionsThese data show that double-dose vaccination induced in patients with SARDs anti-RBD IgG and IgA antibodies in amounts not significantly different from controls, and, most interestingly, characterised by high avidity and endowed with neutralising activity.

Clinical Trial registry name and registration number: Zeus study, NCT02403115

Background: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). Aim: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. Patients and methods: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria

At the beginning of COVID-19, we underlined that this pandemic was a new challenge for rheumatologists. On the one hand, it was necessary to clarify the impact of this new viral disease on the natural history of many rheumatic diseases and, on the other hand, to define the beneficial or harmful effects of the synthetic or targeted therapies used for their treatment. In addition, we have postulated that in view of the common pathogenetic mechanisms involved, the therapeutic armamentarium currently employed in the management of viral or idiopathic systemic autoimmune rheumatic diseases could be useful to control the "cytokine storm" induced by SARS-COV-2. One year later, in the present review we have analysed the progress of the knowledge on both these aspects and updated the algorithms initially proposed for a rational use of the synthetic and targeted anti-inflammatory and immunomodulatory agents in the management of COVID-19.

despite the absence of specific guidelines, the treatment with intravenous immunoglobulins (IvIg) is considered effective in patients with refractory idiopathic inflammatory myopathies (IIM). The aim of our study is to evaluate the effectiveness and the safety of IvIg and define the possible profile of IIM patients candidate to IvIg treatment.we performed a retrospective study of IIM pts. treated with IvIg (2 g/kg/month). We collected demographic, epidemiological, laboratory and clinical data. Additionally, to evaluate the toxicity, the adverse events occurred during the treatment were collected.123 patients with IIM were included in the study. The main indications for the prescription of IvIg were muscle (83.7% of patients) and esophageal involvement (45.5% of patients). IvIg were started mainly for refractory disease. At the end of treatment (mean duration 14 months), muscular necrosis enzymes decreased significantly and dysphagia VAS decreased significantly (p 0.001), while MMT value increased (104.6 ± 24.2 vs. 127.0 ± 22.2 p 0.001). Ninety-six pts. (78%) responded to IvIg. They had a shorter disease duration (p 0.001), higher creatine kinase levels (p 0.001), and higher prevalence of myalgias at the baseline (p = 0.023) compared to non-responders. The presence of Raynaud's phenomenon (p = 0.023-odds ratio 0.28 [0.11-0.72]) and skin involvement (p = 0.004, odds ratio 0.18 [0.06-0.55]), were associated to a worse response. Adverse events were mostly mild and transitory.Despite their high cost, IvIg confirmed their effectiveness in refractory IIM pts., particularly in muscular and esophageal manifestations. Specific clinical characteristics at the baseline may identify the patients with higher probability of response to the treatment.

ObjectiveTo report the results of a survey exploring the experience of patients with SLE facing hydroxychloroquine (HCQ) shortage that occurred during the early phases of the COVID-19 pandemic.MethodsA survey was designed by Lupus Europe’s patient advisory network and distributed through its social media, newsflash and members' network. People with lupus were asked about their last HCQ purchases and their level of anxiety (on a 0–10 scale) with regard to not being able to have access to HCQ, once in April 2020 (first wave) and after 11 August (second wave). The results were compared.Results2075 patients responded during the first wave; 1001 (48.2%) could get HCQ from the first place they asked, 230 (11.1%) could get the drug by going to more than one pharmacy, 498 (24.0%) obtained HCQ later from their usual pharmacy and 126 (6.1%) from other sources. 188 (9.1%) could not get any; 32 (1.5%) did not respond to this question. All countries showed significant improvement in HCQ availability during the second wave. 562 (27.4%) patients reported an extremely high level of anxiety in wave 1 and 162 (10.3%) patients in wave 2; 589 (28.7%) and 268 (17.1%) patients reported a high level of anxiety in wave 1 and wave 2, respectively.ConclusionsThe HCQ shortage had a significant impact on patients with SLE and has been responsible for psychological consequences including anxiety. Indeed, despite an objective improvement in drug availability, the event is leaving significant traces in patients’ mind and behaviours.

Immunological tolerance is a critical feature of the immune system; its loss might lead to an abnormal response of lymphocytes causing autoimmune diseases. One of the most important groups belonging to autoimmune disorders is the connective tissue diseases (CTD). CTD are classified among systemic rheumatic diseases and include pathologies such as systemic lupus erythematosus (SLE), and undifferentiated CTD (UCTD). In this study, we evaluated oxidative and genome damage in peripheral blood lymphocytes from patients with SLE and UCTD, further classified on the basis of disease activity and the presence/absence of a serological profile. Oxidative damage was evaluated in cell membrane using the fluorescent fatty acid analogue BODIPY581/591 C11. The percentage of oxidised lymphocytes in both SLE and UCTD patients was higher than in the control group, and the oxidative stress correlated positively with both disease activity and autoantibody profile. The γH2AX focus assay was used to quantify the presence of spontaneous double strand breaks (DSBs), and to assess the abilities of DSBs repair system after T cells were treated with mitomycin C (MMC). Subjects with these autoimmune disorders showed a higher number of γH2AX foci than healthy controls, but no correlation with diseases activity and presence of serological profile was observed. In addition, patients displayed an altered response to MMC-induced DSBs, which led their peripheral cells to greatly increase apoptosis. Taken together our results confirmed an interplay among oxidative stress, DNA damage and impaired DNA repair, which are directly correlated to the aggressiveness and clinical progression of the diseases. We propose the evaluation of these molecular markers to better characterise SLE and UCTD, aiming to improve the treatment plan and the quality of the patients’ life.

Funder: American College of Rheumatology Research and Education Foundation; FundRef: http://dx.doi.org/10.13039/100000960, Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases; FundRef: http://dx.doi.org/10.13039/100000069, Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to

Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, Objective: To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria 1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.

ObjectivesRemission in systemic lupus erythematosus (SLE) is defined through a combination of ‘clinical SLE Disease Activity Index (cSLEDAI)=0’, ‘physician's global assessment (PGA) MethodsWe tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA ResultsWe included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA ConclusionscSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.

IntroductionThe European Reference Network (ERN) ReCONNET is the ERN aimed at improving the management of rare and complex connective tissue and musculoskeletal diseases (rCTDs) across the European Union (EU). In the mission of ERN ReCONNET, clinical practice guidelines (CPGs) play a crucial role, representing a valid tool towards the harmonisation of the management of rCTDs while improving effectiveness and quality of care delivered to patients.MethodsERN ReCONNET developed two surveys to map the adherence to rCTDs CPGs among healthcare providers and to assess the knowledge and awareness of CPGs for their diseases among patients, family members and caregivers.ResultsThe results of the surveys highlighted that healthcare professionals find it useful to apply CPGs in clinical practice (93%), while 62% of them experience difficulties and barriers in the application in their centres. Healthcare professionals also highlighted the need to develop CPGs for all rCTDs and to implement the use of the existing CPGs in clinical practice. On the other hand, patients, families and caregivers are relatively aware of the purpose of CPGs (51%) and 62% of them were aware of the existence of CPGs for their disease. Patient-friendly versions of CPGs and patients’ lifestyle guidelines should be systematically developed contributing to the empowerment of patients in the disease management.ConclusionERN ReCONNET is addressing the main issues identified in the results of the survey, promoting practical actions for the local adaptation of CPGs across Europe, improving their routine clinical use and increasing the awareness on CPGs among rCTDs patients, family members and caregivers.

This study was aimed at assessing the impact of a non-medical recommendation on drug-utilisation patterns and clinical outcomes in a central Region of Italy (Tuscany).We performed a pre-post study on data collected in Tuscan healthcare administrative databases. We included patients with diagnosis of rheumatoid arthritis, or psoriatic arthritis, or ankylosing spondylitis, or ulcerative colitis, or Crohn's disease, or psoriasis. The first analysis compared patients treated with infliximab on January 1st, 2013 (originator only available) to those on January 1st, 2016 (both originator and biosimilar available). The second analysis compared infliximab-originator users with infliximab-biosimilar ones. Adjusted odds ratios (OR) of persistence on treatment, Emergency Department (ED) admissions, hospitalisations and specialist visits were calculated.The first analysis included 606 patients and the second 434. In both analyses, we did not observe any significant difference in persistence. In the first analysis, the 2016 infliximab-originator cohort showed a significant association with the risk of having at least one ED admission (OR 1.54, 95% CI 1.02 to 2.31). A significant difference of accessing a specialist visit (more frequently rheumatologic) was observed in the 2016 cohort (OR 1.52, 95% CI 1.05 to 2.20). In the second analysis, the risk of having at least one hospitalisation decreased significantly in switchers to infliximab-biosimilar (OR 0.49, 95% CI 0.26 to 0.96).Our study showed no relevant changes in the clinical outcomes following the introduction of infliximab-biosimilar. The few observed differences observed can be explained mainly by a selective switching to infliximab-biosimilar in patients with lower burden of disease.

Objective To investigate predictors of response, remission, low disease activity, damage, and drug discontinuation in patients with systemic lupus erythematosus (SLE) who were treated with belimumab. Methods In this retrospective study of a multicenter cohort of SLE patients who received intravenous belimumab, the proportion of patients who achieved remission, low disease activity, and treatment response according to the SLE Responder Index 4 (SRI-4) was determined, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) was used to score disease damage yearly over the follow-up. Predictors of outcomes were analyzed by multivariate logistic regression with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Results The study included 466 patients with active SLE from 24 Italian centers, with a median follow-up period of 18 months (range 1-60 months). An SRI-4 response was achieved by 49.2%, 61.3%, 69.7%, 69.6%, and 66.7% of patients at 6, 12, 24, 36, and 48 months, respectively. Baseline predictors of response at 6 months included a score of ≥10 on the SLE Disease Activity Index 2000 (SLEDAI-2K) (OR 3.14 [95% CI 2.033-4.860]) and a disease duration of ≤2 years (OR 1.94 [95% CI 1.078-3.473). Baseline predictors of response at 12 months included a score of ≥10 on the SLEDAI-2K (OR 3.48 [95% CI 2.004-6.025]) and an SDI score of 0 (OR 1.74 [95% CI 1.036-2.923]). Baseline predictors of response at 24 months included a score of ≥10 on the SLEDAI-2K (OR 4.25 [95% CI 2.018-8.940]) and a disease duration of ≤2 years (OR 3.79 [95% CI 1.039-13.52]). Baseline predictors of response at 36 months included a score of ≥10 on the SLEDAI-2K (OR 14.59 [95% CI 3.54-59.79) and baseline status of current smoker (OR 0.19 [95% CI 0.039-0.69]). Patients who were in remission for ≥25% of the follow-up period (44.3%) or who had low disease activity for ≥50% of the follow-up period (66.1%) accrued significantly less damage (P = 0.046 and P = 0.007). A baseline SDI score of 0 was an independent predictor of achieving low disease activity in ≥50% of the follow-up period and remission in ≥25% of the follow-up period. Our findings suggest that the lower the baseline damage, the greater the probability of achieving remission over the course of ≥25% of the follow-up. Further, there was a negative association between the number of flares reported prior to belimumab initiation and the frequency of belimumab discontinuation due to inefficacy (P = 0.009). Conclusion In patients with active SLE and low damage at baseline, treatment with belimumab early in the disease may lead to favorable outcomes in a real-life setting.

OBJECTIVE Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. METHODS Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of

Background:The consequences of the COVID-19 outbreak are unprecedented and have been felt by everyone around the world, including people with rheumatic and musculoskeletal diseases (RMDs). With the development of vaccines, the future is becoming brighter. Vaccines are a key pillar of public health and have been proven to prevent many serious diseases. However, vaccination also raises questions, especially for patients with inflammatory RMDs and/or treated with drugs that influence their immune system.Objectives:Our aim was to collect safety data among RMD patients receiving COVID-19 vaccines.Methods:The EULAR COVID-19 Vaccination (COVAX) Registry is an observational registry launched on 5 February 2021. Data are entered voluntarily by clinicians or associated healthcare staff; patients are eligible for inclusion if they have an RMD and have been vaccinated against SARS-CoV-2. Descriptive statistics are presented.Results:As of 27 April 2021, 1519 patients were reported to the registry. The majority were female (68%) and above the age of 60 (57%). Mean age was 63 years (SD 16), ranging from 15 to 97 years. A total of 28 countries contributed to the registry, with France (60%) and Italy (13%) as the highest contributors. The majority (91%) had inflammatory RMDs. Inflammatory joint diseases accounted for 51% of cases, connective tissue diseases 19%, vasculitis 16%, other immune mediated inflammatory diseases 4%, and non-inflammatory/mechanical RMDs 9%. The most frequent individual diagnoses were rheumatoid arthritis (30%), axial spondyloarthritis (8%), psoriatic arthritis (8%), systemic lupus erythematosus (SLE, 7%) and polymyalgia rheumatica (6%). At the time of vaccination, 45% were taking conventional synthetic DMARDs, 36% biological DMARDs, 31% systemic glucocorticoids, 6% other immunosuppressants (azathioprine; mycophenolate; cyclosporine; cyclophosphamide; tacrolimus), and 3% targeted synthetic DMARDs. The most frequent individual DMARDs were methotrexate (29%), TNF-inhibitors (18%), antimalarials (10%) and rituximab (6%). The vaccines administered were: 78% Pfizer, 16% AstraZeneca, 5% Moderna and 1% other/unknown; 66% of cases received two doses and 34% one dose. Mean time from 1st and 2nd dose to case report was 41 days (SD 26) and 26 days (SD 23), respectively. COVID-19 diagnosis after vaccination was reported in 1% (18/1519) of cases. Mean time from first vaccination until COVID-19 diagnosis was 24 days (SD 17). Disease flares were reported by 5% (73/1375) of patients with inflammatory RMDs, with 1.2% (17/1375) classified as severe flares. Mean time from closest vaccination date to inflammatory RMD flare was 5 days (SD 5). The most common flare types were arthritis (35/1375=2.5%), arthralgia (29/1375=2.1%), cutaneous flare (11/1375=0.8%) and increase in fatigue (11/1375=0.8%). Potential vaccine side effects were reported by 31% of patients (467/1519). The majority were typical early adverse events within 7 days of vaccination, namely pain at the site of injection (281/1519=19%), fatigue (171/1519=11%) and headache (103/1519=7%). Organ/system adverse events were reported by 2% (33/1519) but only 0.1% (2/1519) reported severe adverse events, namely a case of hemiparesis in a patient with systemic sclerosis/SLE overlap syndrome (ongoing at the time of reporting), and a case of giant cell arteritis in a patient with osteoarthritis (recovered/resolved without sequelae).Conclusion:The safety profiles for COVID-19 vaccines in RMD patients was reassuring. Most adverse events were the same as in the general population, they were non-serious and involved short term local and systemic symptoms. The overwhelming majority of patients tolerated their vaccination well with rare reports of inflammatory RMD flare (5%; 1.2% severe) and very rare reports of severe adverse events (0.1%). These initial findings should provide reassurance to rheumatologists and vaccine recipients, and promote confidence in COVID-19 vaccine safety in RMD patients, namely those with inflammatory RMDs and/or taking treatments that influence their immune system.Acknowledgements:EULAR COVID-19 Task Force; European Reference Network on rare and Complex Connective Tissue and Musculoskeletal Diseases; European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases Network; all rheumatologists contributing to the EULAR COVAX Registry.Disclosure of Interests:Pedro M Machado Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript., Grant/research support from: Orphazyme, unrelated to this manuscript., Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript., Saskia Lawson-Tovey: None declared, Kimme Hyrich Grant/research support from: BMS, UCB, and Pfizer, all unrelated to this manuscript., Speakers bureau: Abbvie, Loreto Carmona Consultant of: her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, S.A., Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal GmbH, and UCB Pharma, all unrelated to this manuscript., Laure Gossec Grant/research support from: AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, UCB, all unrelated to this manuscript., Speakers bureau: Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi, Galapagos, all unrelated to this manuscript., Elsa Mateus Grant/research support from: LPCDR received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal S.A., MSD, Celgene, Medac, Pharmakern, GAfPA; grants and non-financial support from Pfizer; non-financial support from Grünenthal GmbH, outside the submitted work., Anja Strangfeld Speakers bureau: AbbVie, MSD, Roche, BMS, and Pfizer, all unrelated with this manuscript., BERND RAFFEINER: None declared, Tiphaine Goulenok: None declared, Olilvier Brocq: None declared, Martina Cornalba: None declared, José A Gómez-Puerta Speakers bureau: AbbVie, BMS, GSK, Janssen, Lilly, MSD, Roche and Sanofi., Eric Veillard: None declared, Ludovic Trefond: None declared, Jacques-Eric Gottenberg: None declared, Julien Henry: None declared, Patrick Durez: None declared, Gerd Rüdiger Burmester: None declared, Marta Mosca: None declared, Eric Hachulla: None declared, Hans Bijlsma: None declared, Iain McInnes: None declared, Xavier Mariette Consultant of: BMS, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sanofi-Aventis, UCB, and grant from Ose, all unrelated to this manuscript.

Background:LN is still a severe manifestation of Systemic lupus erythematosus (SLE) and multitarget therapy is needed to control the disease especially in refractory cases.Objectives:To evaluate renal response in SLE patients with glomerulonephritis (GN) treated with Belimumab in real-life setting.Methods:Patients with proteinuria >0.5 g/24 h and/or active sediment at baseline enrolled in a multicentre Italian cohort of SLE patients (BeRLiSS study), treated with monthly iv Belimumab 10 mg/kg plus standard of care were considered in this study. Complete renal response (CRR) was defined as proteinuria 2 and no rescue therapy. Primary efficacy renal response (PERR) was defined as proteinuria ≤0.7 g/24 h, eGFR ≥60ml/min/1.73m2 and no rescue therapy. Prevalence and predictive factors of CRR and PERR at 12 and 24 months after Belimumab initiation were analyzed by multivariate logistic regression analysis.Results:A total of 91 patients were considered in this study, 79 female, mean age 40.51±9.03 years, mean disease duration 12.18±8.15 years, median follow-up time after Belimumab initiation 22 months. Twenty patients had baseline proteinuria ≥0.5 2 at baseline. Immunosuppresants were taken by 70 (76.9%) patients: 47 micofenolate, 15 azathioprine and 5 ciclosporine. Sixty patients (65.9%) were on antimalarials. During follow-up 34 (37.4%) patients achieved CRR. Among them 5 (14.7%) patients relapsed and 29 (85.3%) patients maintained remission. Mean time to achieved CRR was 9.71±5.91 months.High levels of baseline proteinuria were a negative independent predictor of CRR and PERR at 6 months (OR 0.044 CI95% 0.006-0.320 p=0.002 and OR 0.232 CI95% 0.091-0.596 p=0.002) and 12 months (OR 0.029 CI95% 0.002-0.556 p=0.019 and OR 0.056 CI95% 0.009-0.327 p=0.001). High levels of baseline creatinine were a negative independent predictor of renal response. Renal response at 6 months was a strong predictive factor of renal response at 12 and 24 months.Conclusion:Belimumab is an effective add-on therapy in the treatment of GN in real-life practice setting.Disclosure of Interests:None declared

Objective Pre-clinical and uncontrolled studies in patients with systemic lupus erythematosus (SLE) showed that mesenchymal stromal cells (MSCs) have a potential therapeutic role in refractory cases. The optimal therapeutic strategy in these patients remain to be elucidated. Our aim was to test the hypothesis that repeated administrations of 1×106/kg body weight of allogenic MSCs, that is a significantly lower dosage with respect to the fixed 1×106 MSC used in animal models, can be effective in improving the clinical course of a murine SLE model. Methods Bone marrow derived MSCs were obtained from 12-week-old C57BL/6J mice. Seventy-five 8 weeks old female NZ mice were randomly assigned to receive via caudal vein the following alternative treatments: 1) single infusion of 106 MSCs/kg body weight at 18 weeks of age (NZs18) or at at 22 weeks of age (NZs22); 2) multiple monthly infusions of 106 MSCs/kg body weight starting at 18 weeks of age (NZM18) or at 22 weeks of age (NZM22); 3) saline infusions (NZc) Fifteen 8 weeks old C57BL/6J mice (Envigo, Huntingdon, UK) were used as untreated controls (C). Weekly, body weight was recorded and twenty-four hour urines were collected by metabolic cages for each animal; proteinuria was detected by dipstick analysis. At sacrifice, peripheral blood samples were collected from mice and anti-dsDNA antibodies were detected by enzyme immunoassorbent assay (ELISA) method using commercial kits. At sacrifice, kidneys were analyzed for histopathology and immunohistochemical analysis for B220, CD4, MPO, CD4+Foxp3, F40/80 infiltration was performed. Results Proteinuria occurrence was delayed NZS and NZM mice, no differences were observed in anti-dsDNA autoantibody titer among the groups at the different time-points; at 36 weeks, no significant differences were observed in term of nephritis scores. Inflammatory cells deposition (MPO and F4/80 positive cells) in NZM was significantly higher than in NZ and NZS. An overexpression of B lymphocytes (B220) was found in NZM while T regulatory cells (CD4+ Foxp3+ cells) were reduced in both NZS and NZM with respect to NZc. Conclusions Overall, our study failed to show a positive effect of a treatment with murine MSCs in this model and, for some aspects, even deleterious results seem to be observed.

Introduction Although often asymptomatic, cardiac involvement is common in systemic sclerosis (SSc), and is associated with an increased morbidity and mortality. The aim of this study is to investigate whether high-sensitivity troponin (HSTn) might represent a useful tool to detect subclinical scleroderma heart involvement (SHI) in SSc. Methods We enrolled 65 consecutive SSc patients who performed HSTn test, electrocardiogram and an echocardiogram within six months of HSTn test. We acquired also data about N-terminal segment of proBNP (NT-proBNP) and cardiac magnetic resonance imaging (cMRI). We excluded patients with overt pulmonary arterial hypertension. We defined as subclinical SHI the presence of the following conditions: diastolic dysfunction, pericardial effusion, conduction abnormalities/arrhythmias, oedema and/or T2 weighted non-ischemic pattern showed by cMRI. Results Twelve patients showed SHI, and 23 and 29, respectively, had high levels of HSTn and of NT-proBNP. SHI is correlated with high levels of HSTn (p = 0.02) with a significant difference between HSTn values in patients with or without SHI (59 vs. 13 ng/mL; p = 0.0097). Moreover, among patients with abnormal NT-proBNP, 18 also had out of range HSTn (Spearman rank correlation 0.5; pConclusions Our data show a close relationship between HSTn and NT-proBNP in SSc patients with SHI. HSTn might be a marker of SHI while NT-proBNP seems to be less specific for heart dysfunction.

ObjectivesTreat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.MethodsAn international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.ResultsThe task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.ConclusionsThe work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

Background This proof of concept study was aimed at characterizing novel salivary biomarkers specific for different subsets in primary Sjögren’s syndrome (pSS) in order to improve patients’ profiling. Methods pSS patients were stratified in three subgroups according to both (a) focus score in the minor salivary gland biopsies (i.e. intensity of immune cell infiltration in the tissue) and (b) unstimulated salivary flow rate. Healthy volunteers were included as controls. A nano-HPLC-SWATH-MS approach was used for the analysis of saliva proteome of different subsets. Results We found 203 differentially expressed proteins in pSS patients with respect to controls with evident differences in the expression of normal constituents of the human salivary proteome (i.e. prolactin-inducible protein, proline-rich proteins, cystatins) and several mediators of inflammatory processes. The comparative analysis of the pSS phenotypes unrevealed 63 proteins that were shared and specifically modulated in the three subsets of pSS patients converging on several inflammatory pathways. Among them S100A protein appeared of particular interest merging on IL-12 signaling and being significantly influenced by either salivary flow impairment or intensity of immune cell infiltration in the tissue. Conclusions Constellations of proteins, including S100A proteins, characterize different pSS subsets reflecting either salivary gland dysfunction or inflammation. Salivary proteomics may foster future research projects ultimately aimed at developing personalized treatments for pSS patients. Electronic supplementary material The online version of this article (10.1186/s12014-019-9245-1) contains supplementary material, which is available to authorized users.