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Objectives The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. Methods Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. Results Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. Conclusion In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use.

BACKGROUND: Recurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear.AIM: To determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares.METHODS: A multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS.RESULTS: Eighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE.CONCLUSION: Antiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk.

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.

Objective Electronic health records (EHR) are increasingly being recognized as a major source of data reusable for medical research and quality monitoring, although patient identification and assessment of symptoms (characterization) remain challenging, especially in complex diseases such as systemic lupus erythematosus (SLE). Current coding systems are unable to assess information recorded in the physician's free-text notes. This study shows that text mining can be used as a reliable alternative. Methods In a multidisciplinary research team of data scientists and medical experts, a text mining algorithm on 4607 patient records was developed to assess the diagnosis of 14 different immune-mediated inflammatory diseases and the presence of 18 different symptoms in the EHR. The text mining algorithm included key words in the EHR, while mining the context for exclusion phrases. The accuracy of the text mining algorithm was assessed by manually checking the EHR of 100 random patients suspected of having SLE for diagnoses and symptoms and comparing the outcome with the outcome of the text mining algorithm. Results After evaluation of 100 patient records, the text mining algorithm had a sensitivity of 96.4% and a specificity of 93.3% in assessing the presence of SLE. The algorithm detected potentially life-threatening symptoms (nephritis, pleuritis) with good sensitivity (80%-82%) and high specificity (97%-97%). Conclusion We present a text mining algorithm that can accurately identify and characterize patients with SLE using routinely collected data from the EHR. Our study shows that using text mining, data from the EHR can be reused in research and quality control.

Monoclonal gammopathy of renal significance (MGRS) encompasses a group of disorders in which a monoclonal immunoglobulin (M-protein) secreted by a B-cell or plasma cell clone causes renal disease. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of MGRS where M-protein is deposited in the glomerulus. Although evidence is limited, the current consensus is that therapy for PGNMID should be directed against the underlying clone. However, it is conceivable that there is heterogeneity in the renal prognosis of PGNMID and that not all patients have need for clone-directed therapy. Here, we report two cases of PGNMID with IgM-kappa gammopathy. In one case of a 53-year-old woman the glomerulonephritis resolved without clone-directed therapy. In the other case of a 34-year-old woman clone-directed therapy was discontinued due to adverse effects. Although no hematological response was achieved, the PGNMID resolved. In both cases there are no signs of a recurrent glomerulonephritis in over 3 years of follow-up. Here, we review the literature and suggest that some PGNMID patients have a favorable renal prognosis in whom clone-directed therapy can be withheld or postponed. Further research is warranted to yield predictors to identify these patients and to better understand the disease course of PGNMID.

Reliable early ascertainment in patients with SLE is important to prevent the accumulation of irreversible organ damage. Autoantibodies are often present in the serum of patients before the first symptoms arise, therefore they are of potential use as early diagnostic tools.We used a custom-made antibody microarray containing 57 autoantigens to analyze serum samples of 1519 patients previously tested for anti-dsDNA and 361 samples of self-reported healthy blood bank donors (BBD). The 1519 patients included 483 patients with SLE, 346 patients with other immune mediated inflammatory diseases (IMID), 218 patient controls without relevant clinical symptoms (Non-IMID), and 472 patients that did not fit in any of the previous groups (Rest). The Non-IMID and BBD groups were used individually to create multivariable prediction models to distinguish samples of patients with SLE from these control groups. We subsequently used these models to predict the outcome for samples of patients who developed SLE while in follow-up (pre-SLE).Out of 1036 patients with no diagnosis of SLE at the moment of sample collection, 17 patients developed SLE while in follow-up (mean time to diagnosis 7.2 months). The best performing model (AUC 0.83) identified 9 out of 17 (53%) pre-SLE samples as SLE, with a specificity of 94%.Serum samples of patients who will develop SLE in the future already show a shift of the autoantibody profile prior to diagnosis. In this study, we show that these autoantibody profiles can be used to identify these future SLE 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.

© 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.

ObjectiveMany autoantibodies are known to be associated with SLE, although their role in clinical practice is limited because of low sensitivity and weak associations with clinical manifestations. There has been great interest in the discovery of new autoantibodies to use in clinical practice. In this study, we investigated 57 new and known antibodies and their potential for diagnostics or risk stratification.MethodsBetween 2014 and 2017, residual sera of all anti-dsDNA tests in the UMC Utrecht were stored in a biobank. This included sera of patients with SLE, patients with a diagnosis of another immune-mediated inflammatory disease (IMID), patients with low (non-IMID) or medium levels of clinical suspicion of SLE but no IMID diagnosis (Rest), and self-reported healthy blood bank donors. Diagnosis and (presence of) symptoms at each blood draw were retrospectively assessed in the patient records with the Utrecht Patient-Oriented Database using a newly developed text mining algorithm. Sera of patients were analysed for the presence of 57 autoantibodies with a custom-made immunofluorescent microarray. Signal intensity cut-offs for all antigens on the microarray were set to the 95th percentile of the non-IMID control group. Differences in prevalence of autoantibodies between patients with SLE and control groups were assessed.ResultsAutoantibody profiles of 483 patients with SLE were compared with autoantibody profiles of 1397 patients from 4 different control groups. Anti-dsDNA was the most distinguishing feature between patients with SLE and other patients, followed by antibodies against Cytosine-phosphate-Guanine (anti-CpG) DNA motifs (pSaccharomyces cerevisiaeantibodies) were more prevalent in patients with SLE with (a history of) lupus nephritis than patients with SLE without nephritis.ConclusionAntibodies against CpG DNA motifs are prevalent in patients with SLE. Anti-CMV antibodies are associated with lupus nephritis.

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.

OBJECTIVE To identify and assess the magnitude of effect of pregnancy outcome predictors in women with antiphospholipid syndrome (APS) by means of systematic review and meta-analysis. METHODS PubMed and Embase were searched (13th June 2020) for studies reporting on pre-pregnancy risk factors of pregnancy outcomes in APS patients. Literature screening and data extraction were conducted by two reviewers independently, in a blinded standardized manner. Pooled univariate odds ratios (OR) were computed using a random effects model. Heterogeneity was assessed by I2%. RESULTS The search yielded 3013 unique results; 27 records were included in this meta-analysis. Previous thrombosis was associated with a decreased live birth risk (OR 0.60, p

Low-dose radiation therapy (LD-RT) has historically been a successful treatment for pneumonia and is clinically established as an immunomodulating therapy for inflammatory diseases. The ongoing COVID-19 pandemic has elicited renewed scientific interest in LD-RT and multiple small clinical trials have recently corroborated the historical LD-RT findings and demonstrated preliminary efficacy and immunomodulation for the treatment of severe COVID-19 pneumonia. The present review explicates archival medical research data of LD-RT and attempts to translate this into modernized evidence, relevant for the COVID-19 crisis. Additionally, we explore the putative mechanisms of LD-RT immunomodulation, revealing specific downregulation of proinflammatory cytokines that are integral to the development of the COVID-19 cytokine storm induced hyperinflammatory state. Radiation exposure in LD-RT is minimal compared to radiotherapy dosing standards in oncology care and direct toxicity and long-term risk for secondary disease are expected to be low. The recent clinical trials investigating LD-RT for COVID-19 confirm initial treatment safety. Based on our findings we conclude that LD-RT could be an important treatment option for COVID-19 patients that are likely to progress to severity. We advocate the further use of LD-RT in carefully monitored experimental environments to validate its effectiveness, risks and mechanisms of LD-RT.

Introduction Patients with the antiphospholipid syndrome on anticoagulant therapy can be monitored with the INR using Point Of Care (POC) devices. However, INR values could be falsely elevated due to antiphospholipid-antibodies using POC devices. Previous studies that have compared INR values measured with POC devices and a laboratory coagulometer in APS patients varied in the methods, which makes the interpretation of the results difficult. We have, therefore, conducted this single center study to investigate whether INR values in APS patients measured with the most commonly used POC device (CoaguChek) in the Netherlands are comparable with whole blood INR values in our laboratory in the UMC Utrecht. Methods INR values measured by the CoaguChek and by the coagulometer in our laboratory measured with the Owren method using a rabbit brain derived thromboplastin were compared in 20 consecutive APS patients. A paired students T-test was performed to compare both means and a p value 0,5 was considered clinically significant. Results No statistically significant difference between the INR measured with the CoaguChek and the coagulometer in our laboratory was found (p >0,05). Furthermore, an acceptable correlation was found in the linear regression analysis (r=0,893). However, in 3 patients with triple antiphospholipid antibody positivity, a clinically relevant difference in the INR was found (>0,5). Conclusion In conclusion, the CoaguChek generates comparable results with the coagulometer in our clinic. However, in a subset of patients with triple positivity the CoaguChek show a clinical relevant difference. Therefore, results of the CoaguChek in this group of patients should be interpreted with caution.

Background Many autoantibodies are known to be associated with SLE, although their role in clinical practice is limited because of low sensitivity and weak associations with clinical manifestations. Therefore, there has been great interest in the discovery of new autoantibodies or autoantibody patterns for clinical practice. In this study, we investigated patterns of new and known antibodies and their possible role in diagnostics or risk stratification. Methods Between 2014 and 2017, residual sera of all anti-dsDNA tests in the UMC Utrecht were stored in a biobank. Diagnosis and presence of symptoms at each blood draw were retrospectively assessed in the patient records with the Utrecht Patient-Oriented Database (UPOD) using a newly developed text mining algorithm. Sera from a balanced cohort of patients with different diagnoses and patients without an assigned diagnosis were analyzed for the presence of 74 autoantibodies by a custom-made immunofluorescent microarray. Whenever possible, results were compared to corresponding historic in-house tests to assess quality. Differences in autoantibodies between patients with SLE and patients with a low suspicion of SLE were investigated by univariate and machine learning (XGBoost) analyses. Results Autoantibody profiles of 484 patients with SLE were compared to 218 controls. Results from the microarray corresponded well with those from corresponding validated assays (AUC 0.726–0.902). Both univariate and machine learning analysis showed anti-dsDNA as most distinctive feature between both groups. Moreover, antibodies against Cytosine-phosphate-Guanine (anti-CpG) DNA motifs were found to be strongly associated with SLE (p Conclusions Anti-CpG antibodies are prevalent in patients with SLE and are associated with Lupus Nephritis independent of anti-dsDNA, suggesting an additive diagnostic value of anti-CpG antibodies. Acknowledgements This project was supported by Thermo Fisher Scientific.

Purpose This study aims to gain insight into the care provided to patients with antiphospholipid syndrome (APS) in The Netherlands and to identify areas for improvement from the perspective of both patients and clinicians. Methods APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were identified using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to examine differences in medical practice, medical records were reviewed retrospectively regarding clinical and laboratory manifestations, pharmacological treatment and management of disease in six hospitals throughout The Netherlands. Results Fourteen interviewed medical specialists, fourteen focus group participants and 79 survey respondents participated in the study. 237 patients were included in medical record review. Only one-third of patients were diagnosed with APS within three months after entering specialist care. Diagnosis and management varied between centres and specialists. Almost 10% of triple positive patients did not receive any treatment at the time of medical record review. Major challenges according to specialists and patients were poor recognition of APS by health care professionals, fragmentation of care and lack of accessible, reliable patient education and psychosocial support. Conclusion This study describes delayed diagnosis, variability in management strategies and a burden placed on patients to orchestrate their own care in APS care in The Netherlands. Of note, almost 10% of triple positive patients did not receive any treatment, despite this group of patients being at the highest risk of recurrent thrombosis. Acknowledgements This work was supported by the Arthritis Research and Collaboration Hub (ARCH) Foundation.

Introduction The aim of this narrative review is to provide an overview of the literature on the possible immunologic pathophysiology of psychiatric manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). Methods A systematic search on PubMed was conducted. English studies with full text availability that investigated the correlation between blood-brain barrier (BBB) dysfunction, intrathecal synthesis of antibodies, antibodies, cytokines, chemokines, metalloproteinases, complement and psychiatric NPSLE manifestations in adults were included. Results Both transient BBB-dysfunction with consequent access of antibodies to the cerebrospinal fluid (CSF) and intrathecal synthesis of antibodies could occur in psychiatric NPSLE. Anti-phospholipid antibodies, anti-NMDA antibodies and anti-ribosomal protein p antibodies seem to mediate concentration dependent neuronal dysfunction. Interferon-α may induce microglial engulfment of neurons, direct neuronal damage and production of cytokines and chemokines in psychiatric NPSLE. Several cytokines, chemokines and matrix metalloproteinase-9 may contribute to the pathophysiology of psychiatric NPSLE by attracting and activating Th1-cells and B-cells. Discussion This potential pathophysiology may help understand NPSLE and may have implications for the diagnostic management and therapy of psychiatric NPSLE. However, the presented pathophysiological model is based on correlations between potential immunologic etiologies and psychiatric NPSLE that remain questionable. More research on this topic is necessary to further elucidate the pathophysiology of NPSLE.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of connective tissue diseases, collectively known as myositis. Diagnosis of IIM is challenging while timely recognition of an IIM is of utter importance considering treatment options and otherwise irreversible (severe) long-term clinical complications. With the EULAR/ACR classification criteria (2017) considerable advancement has been made in the diagnostic workup of IIM. While these criteria take into account clinical parameters as well as presence of one autoantibody, anti-Jo-1, several autoantibodies are associated with IIM and are currently evaluated to be incorporated into classification criteria. As individual antibodies occur at low frequency, the development of line blots allowing multiplex antibody analysis has improved laboratory diagnostics for IIM. The Euroline myositis line-blot assay (Euroimmun) allows screening and semi-quantitative measurement for 15 autoantibodies, i.e. myositis specific antibodies (MSA) to SRP, EJ, OJ, Mi-2α, Mi-2β, TIF1-γ, MDA5, NXP2, SAE1, PL-12, PL-7, Jo-1 and myositis associated antibodies (MAA) to Ku, PM/Scl-75 and PM/Scl-100. To evaluate the clinical significance of detection and levels of these autoantibodies in the Netherlands, a retrospective analysis of all Dutch requests for extended myositis screening within a 1 year period was performed. A total of 187 IIM patients and 632 non-IIM patients were included. We conclude that frequencies of MSA and MAA observed in IIM patients in a routine diagnostic setting are comparable to cohort-based studies. Weak positive antibody levels show less diagnostic accuracy compared to positive antibody levels, except for anti-NXP2. Known associations between antibodies and skin involvement (anti-MDA5, anti-TIF1-γ), lung involvement (anti-Jo-1), and malignancy (anti-TIF1-γ) were confirmed in our IIM study population. The availability of multiplex antibody analyses will facilitate inclusion of additional autoantibodies in clinical myositis guidelines and help to accelerate diagnosing IMM with rare but specific antibodies., Highlights • Similar frequency of MAA and MSA in diagnostic setting compared to cohort studies. • Positive levels of MSA/MAA show better diagnostic accuracy compared to weak positive levels. • Anti-NXP2 differentiates already at weak positive level between IIM and non-IIM patients. • Anti-TIF1-γ is associated with malignancy and anti-MDA5 and TIF1-γ with skin disease. • Anti-Jo-1 is associated with lung disease.

Overuse of broad-spectrum antibiotics in emergency departments (EDs) results in antibiotic resistance. We determined whether procalcitonin (PCT) -guided therapy can be used to reduce antibiotic regimens in EDs by investigating efficacy, safety and accuracy.This was a non-inferiority multicentre randomized clinical trial, performed in two Dutch hospitals. Adult patients with fever ≥38.2°C (100.8°F) in triage were randomized between standard diagnostic workup (control group) and PCT-guided therapy, defined as standard workup with the addition of one single PCT measurement. The treatment algorithm encouraged withholding antibiotic regimens with PCT0.5 μg/L, and starting antibiotic regimens at PCT ≥0.5 μg/L. Exclusion criteria were immunocompromised conditions, pregnancy, moribund patients, patients72 h after surgery or requiring primary surgical intervention. Primary outcomes were efficacy, defined as number of prescribed antibiotic regimens; safety, defined as combined safety end point consisting of 30 days mortality, intensive-care unit admission, ED return visit within 2 weeks; accuracy, defined as sensitivity, specificity and area-under-the-curve (AUC) of PCT for bacterial infections. Non-inferiority margin for safety outcome was 7.5%.Between August 2014 and January 2017, 551 individuals were included. In the PCT-guided group (n = 275) 200 (73%) patients were prescribed antibiotic regimens, in the control group (n = 276) 212 (77%) patients were prescribed antibiotics (p 0.28). There was no significant difference in combined safety end point between the PCT-guided group, 29 (11%), and control group, 46 (16%) (p 0.16), with a non-inferiority margin of 0.46% (n = 526). AUC for confirmed bacterial infections for PCT was 0.681 (95% CI 0.633-0.730), and for CRP was 0.619 (95% CI 0.569-0.669).PCT-guided therapy was non-inferior in terms of safety, but did not reduce prescription of antibiotic regimens in an ED population with fever. In this heterogeneous population, the accuracy of PCT in diagnosing bacterial infections was poor. TRIAL REGISTRATION IN NETHERLANDS TRIAL REGISTER: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4949.

There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need.An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation 10 days.One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT 0.25 ng/mL, lactate 2.0 mmol/L or CRP 67 mg/L) or clinical score (SOFA 2 points, qSOFA 2 points, NEWS 4 points or CRB-65 2 points) values were characterised by a significantly longer length of hospitalisation (p 0.001), rate of ICU admission (p 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p 0.001), compared to similar subgroups with low MR-proADM concentrations ( 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities.In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

Background The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET) is a virtual Network that aims to improve and standardize the quality of care offered to rCTDs patients in Europe, empower patients, share knowledge and expertise, enhance research, support efficient use of resources. ERN ReCONNET covers 10 rCTDs: APS, UCTD, Idiopathic Inflammatory myopathies, IgG4, MCTD, Systemic sclerosis, Relapsing Polychondritis, SLE, Sjogren and EDS. Objectives Identification of unmet needs in diagnosis, monitoring and management of rCTDs after literature review of existing clinical practice guidelines (CPGs). Methods After the review of existing CPGs, the most relevant unmet needs, both for clinicians and patients, were identified by discussion among the members of the network. Results A considerable number of unmet needs were identified. In particular, the lack of shared classification criteria, of evidence-based CPGs, validated tools for the assessment of treatment response and disease activity/damage are the major unmet needs especially for the rarest rCTDs. Transversal topics for all rCTDs that need to be addressed are the scarcity of EU/international randomised controlled trials, the identification of patient-reported outcomes and non-adherence to treatment, quality of life indicators, the need to develop composite disease activity scores for all rCTDs and specific (inter)national web-based registries. Patients highlighted the need of a more holistic approach to rCTDs, demanding more attention to pain, fatigue and psychological aspects related to the diseases and the promotion of an early diagnosis. Conclusion The identification of rCTDs unmet needs provided a very useful picture on future actions to be undertaken in order to provide a better care to patients. Many activities are ongoing towards these goals in ERN ReCONNET. These will be possible as a result of a EU collaboration among rCTDs stakeholders, the main added value of ERN ReCONNET. Acknowledgement Thanks to all ERN ReCONNET Steering Committe, Healthcare Providers, ePAGs and Team for huge support. Disclosure of Interests Diana Marinello: None declared, Simone Ticciati: None declared, Rosaria Talarico: None declared, Tobias Alexander: None declared, Laurent Arnaud Consultant for: Alexion, Amgen, AstraZeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Novartis, Pfizer, Roche-Chugai, and UCB., Paid instructor for: Alexion, Amgen, AstraZeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Novartis, Pfizer, Roche-Chugai, and UCB., Speakers bureau: Alexion, Amgen, AstraZeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Novartis, Pfizer, Roche-Chugai, and UCB., Lorenzo Cavagna: None declared, Lorenzo Beretta: None declared, Benjamin Chaigne: None declared, Alain Cornet Grant/research support from: No direct financial grants from Pharmaceutical companies, but some grants accrued LUPUS EUROPE does, in the form of Grants or payment for attending advisory boards or providing patient views, Speakers bureau: I have been involved in GSK panels to provide patient perspective. However, the minor service fee obtained accrued to LUPUS EUROPE ratyher than the company, Nathalie Costedoat-Chalumeau: None declared, Rebecca Fischer-Betz Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Charissa Hermine Frank: None declared, Ilaria Galetti: None declared, Jurgen Grunert: None declared, vera guimaraes: None declared, Luca Iaccarino: None declared, Maarten Limper Consultant for: GSK, Roche and Thermofisher, Speakers bureau: GSK and Roche, Fransiska Malfait: None declared, Xavier Mariette Grant/research support from: Servier, Consultant for: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, UCB Pharma, lisa matthews: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, alain meyer: None declared, Simona Rednic: None declared, Vasco Romao: None declared, Carlo Alberto Scire: None declared, Vanessa Smith: None declared, Alberto Sulli: None declared, Farah Tamirou: None declared, Anna Viola Taulaigo: None declared, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Ana Vieira: None declared, Maurizio Cutolo: None declared, Marta Mosca Paid instructor for: GlaxoSmithKline, Lilly, UCB

Background: The relapse rate in antiphospholipid syndrome (APS) remains high, 20% at 5 years in thrombotic APS and 28% in obstetrical APS (1). Hydroxychloroquine (HCQ) appears as an additional therapy, with immunomodulatory and antithrombotic effects (2-5). Objectives: The main aim of this trial is to assess the efficacy of treatment with Hydroxychloroquine in preventing new events in primary antiphospholipid syndrome patients. Methods: We have performed a retrospective multicentre open-labelled study (2002-2018). Results: 812 patients with APS from 53 international centres from 16 countries were included. In all cases, the previous standard treatment was inefficient. The mean follow-up was 20.2 months (8- 144 mo), the mean age 39.5 years old. The type of clinical manifestations is described in figure 1. The obstetrical manifestations were various as described in figure 2. The number of thrombotic events were 190 arterial and 187 venous. Triple antiphospholipid antibody (tAPL) positivity was found in 20% of patients and lupus anticoagulant (LA) in 22%. No bleeding was registered in 99,6% of cases with treatment by HCQ. HCQ use was associated with favourable outcome in 96% of cases (figure 3). In multivariate analysis, age more than 65 years was associated with arterial events (odds-ratio 0.13 95%CI 0.03-0.32, p 0.005). Conclusion: HCQ could be effective in cases of refractory APS but prospective studies are necessary. References: [1] Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, Buonaiuto V, Jacobsen S, Zeher MM, Tarr T, Tincani A, Taglietti M, Theodossiades G, Nomikou E, Galeazzi M, Bellisai F, Meroni PL, Derksen RH, de Groot PG, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quere I, Hachulla E, Vasconcelos C, Fernandez-Nebro A, Haro M, Amoura Z, Miyara M, Tektonidou M, Espinosa G, Bertolaccini ML, Khamashta MA. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011-8. [2] Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015;14:358–62. [3] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, Argolini LM, Kumar R, Pengo V, Meroni PL, Ruffatti A, Tincani A. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65:17-24. [4] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost JTH. 2013;11:1927–9. Disclosure of Interests: Cristina Belizna: None declared, Ljudmila Stojanovich: None declared, Patrick Saulnier: None declared, Francesca Pregnolato: None declared, Jaume Alijotas-Reig: None declared, Enrique Esteve-Valverde: None declared, Omar Latino: None declared, Sebastien Udry: None declared, Natasa Stanisavljevic: None declared, Alexander Makatsariya: None declared, Jamilya Khizroeva: None declared, Maarten Limper Consultant for: GSK, Roche and Thermofisher, Speakers bureau: GSK and Roche, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Laura Andreoli: None declared, Francesca Regola: None declared, Cecilia Chighizola Speakers bureau: Inova Diagnostics, Maria Orietta Borghi: None declared, Sule Apras Bilgen: None declared, Levent Kilic: None declared, Arsene Mekinian: None declared, Valentina Canti: None declared, Katrien Devreese: None declared, Gilberto Pires Rosa: None declared, Laura Damian: None declared, Fatma Said: None declared, Yehuda Shoenfeld: None declared, Ricard Cervera: None declared, Pier Luigi Meroni Consultant for: Inova, Thermofisher, Teofarma, Zahir Amoura: None declared

Background There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need. Methods An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days. Results One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT

International audience; The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3].Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16].Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency.Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial.This trial consists in two parts: a retrospective and a prospective study.The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

Background: Procalcitonin (PCT) is a new biomarker with a higher accuracy in the diagnosis of bacterial infections. Utilization of PCT may reduce the number of unnecessary antibiotics prescribed to patients and consequently may decrease the rise in antibiotic resistance. The aim of this systematic review is to determine if a PCT-guided algorithm can safely reduce the number of antibiotics prescribed to all patients with a suspected of infection in the emergency department (ED). Methods: MEDLINE, EMBASE, Web of Science, COCHRANE central, PubMed publisher, and Google scholar were searched. Two reviewers performed the screening independently. The QUADAS 2 tool was used to assess quality. Results: In total, 1621 articles were screened. Nine articles were included in the analysis. In the 6 studies on adult patients, only patients with respiratory tract infections were investigated. In these studies, a cutoff value of 0.25 mu g/L was used, and PCT-guided therapy reduced the number of prescribed antibiotics significantly. Three studies were on pediatric patients, 2 on fever without source and 1 on respiratory complaints. Procalcitonin-guided therapy did not reduce antibiotic prescription in children. Procalcitonin-guided therapy did not result in an increase in adverse events in any of the studies. Discussion: Procalcitonin-guided therapy in the ED is only studied in subpopulations, where it was effective and safe in adult patients with respiratory tract infections and not effective but safe nonetheless in specific pediatric populations. Nonadherence is a significant problem in prospective PCT-guided therapy studies. There is not enough evidence to use PCT-guided therapy in a general ED population. (C) 2016 Elsevier Inc. All rights reserved.

Macro- and microclimates may have variable impact on dengue incidence in different settings. We estimated the short-term impact and delayed effects of climate variables on dengue morbidity in Curacao. Monthly dengue incidence data from 1999 to 2009 were included to estimate the short-term influences of climate variables by employing wavelet analysis, generalized additive models (GAM) and distributed lag nonlinear models (DLNM) on rainfall, temperature and relative humidity in relation to dengue incidence. Dengue incidence showed a significant irregular 4-year multi-annual cycle associated with climate variables. Based on GAM, temperature showed a U-shape, while humidity and rainfall exhibited a dome-shaped association, suggesting that deviation from mean temperature increases and deviation from mean humidity and rainfall decreases dengue incidence, respectively. Rainfall was associated with an immediate increase in dengue incidence of 4.1% (95% CI: 2.2-8.1%) after a 10-mm increase, with a maximum increase of 6.5% (95% CI: 3.2-10.0%) after 1.5 month lag. A 1 °C decrease of mean temperature was associated with a RR of 17.4% (95% CI: 11.2-27.0%); the effect was inversed for a 1°C increase of mean temperature (RR= 0.457, 95% CI: 0.278-0.752). Climate variables are important determinants of dengue incidence and provide insight into its short-term effects. An increase in mean temperature was associated with lower dengue incidence, whereas lower temperatures were associated with higher dengue incidence.

Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients.

Background Fever is a common symptom in the emergency department(ED). Fever can be caused by bacterial infections, which are treated with antibiotics. Often, bacterial infections cannot be ruled out in the ED using standard diagnostics, and empiric antibiotic treatment is started. Procalcitonin(PCT) is a biomarker for bacterial infections, but its role in an undifferentiated ED population remains unclear. We hypothesize that PCT-guided therapy may reduce antibiotics prescription in undifferentiated febrile ED patients. The primary objectives of this study are to determine a) the efficacy, b) the safety of PCT-guided therapy, and c) the accuracy of the biomarker PCT for bacterial infections. The secondary objective is to study the cost-effectiveness of PCT-guided therapy. Methods/design This is a multicenter noninferiority randomized controlled trial. All adult ED patients with fever(≥38.2 °C) are randomized between standard care with and without the addition of a PCT level, after written informed consent.For efficacy, the reduction of patients receiving antibiotics is calculated, using a superiority analysis: differences between the PCT-guided group and control group are assessed using a Fisher’s exact test, and a multivariable logistic regression analysis to account for the effects of demographic and medical variables on the percentage of febrile patients receiving antibiotics.Safety consists of a composite endpoint, defined as mortality, intensive care admission and ED return visit within 14 days. Noninferiority of PCT will be tested using a one-sided 95 % confidence interval for the difference in the composite safety endpoint between the PCT-guided and control groups using a noninferiority margin of 7.5 %.Accuracy of PCT and CRP for the diagnosis of bacterial infections will be reported, using the sensitivity, specificity, and the area under the receiver-operating-characteristic curve in the definitive diagnosis of bacterial infections. The sample size is 550 patients, which was calculated using a power analysis for all primary objectives. Enrollment of patients started in August 2014 and will last 2 years. Discussion PCT may offer a more tailor-made treatment to the individual ED patient with fever. Prospective costs analyses will reveal the economic consequences of implementing PCT-guided therapy in the ED. This trial is registered in the Dutch trial register NTR4949

Procalcitonin (PCT) has been shown to be of additional value in the work-up of a febrile patient. This study is the first to investigate the additional value of PCT in an Afro-Caribbean febrile population at the emergency department (ED) of a general hospital. Febrile patients were included at the ED. Prospective, blinded PCT measurements were performed in patients with a microbiologically or serologically confirmed diagnosis or a strongly suspected diagnosis on clinical grounds. PCT analysis was performed in 93 patients. PCT levels differentiated well between confirmed bacterial and confirmed viral infection (area under the curve [AUC] of 0.82, sensitivity 85%, specificity 69%, cut-off 0.24 ng/mL), between confirmed bacterial infection and non-infectious fever (AUC of 0.84, sensitivity 90%, specificity 71%, cut-off 0.21 ng/mL) and between all bacterial infections (confirmed and suspected) and non-infectious fever (AUC of 0.80, sensitivity 85%, specificity 71%, cut-off 0.21 ng/mL). C-reactive protein (CRP) levels were shown to be less accurate when comparing the same groups. This is the first study showing that, in a non-Caucasian febrile population at the ED, PCT is a more valuable marker of bacterial infection than CRP. These results may improve diagnostics and eventually decrease antibiotic prescriptions in resource-limited settings.

Objective: First, to determine whether procalcitonin (PCT) significanty adds diagnostic value in terms of sensitivity and specificity to a common set of markers of infection, including C-reactive protein (CRP), at the Emergency Department. Second, to create a simple scoring rule implementing PCT values. Third, to determine and compare associations of CRP and PCT with clinical outcomes. Design: The additional diagnostic value of PCT was determined using multiple logistic regression analysis. A score was developed to help distinguish patients with a culture-proven bacterial infection from patients not needing antibiotic treatment using 16 potential clinical and laboratory variables. The prognostic value of CRP and PCT was determined using Spearman's correlation and logistic regression. Setting: Emergency Department of a 310-bed teaching hospital. Patients: Patients between 18 and 85 years old presenting with fever to the Emergency Department. Interventions: None. Measurements and Main Results: A total of 211 patients were studied (infection confirmed, n = 73; infection likely, n = 58; infection not excluded, n = 46; no infection, n = 34). CRP and chills were the strongest predictors for the diagnosis of bacterial infection. After addition of PCT to these parameters, model fit significantly improved (p = .003). The resulting scoring rule (score = 0.01 * CRP + 2 * chills + 1 * PCT) was characterized by an AUC value of 0.83 (sensitivity 79%; specificity of 71%), which was more accurate than physician judgment or SIRS (systemic inflammatory response syndrome). PCT levels were significantly associated with admission to a special care unit, duration of intravenous antibiotic use, total duration of antibiotic treatment, and length of hospital stay, whereas CRP was related only to the latter two variables. Conclusions: These data suggest that PCT may be a valuable addition to currently used markers of infection for diagnosis of infection and prognosis in patients with fever at the Emergency Department. (Crit Care Med 2010; 38:457-463)

Objectives: The long pentraxin PTX3 is a promising marker of disease severity in severely ill patients. In order to identify patients warranting critical care as quickly as possible, we investigated the value of PTX3 as a biomarker for disease severity in patients presenting with fever at the emergency department. Methods: Levels of PTX3 were measured in 211 febrile patients at the emergency and the levels were linked to markers of disease severity including admittance to a special care unit, bloodstream infection and congestive heart failure. Results: In comparison to median baseline levels of 2.30 ng/ml (interquartile range 1.66-3.67 ng/ml), levels of PTX3 were significantly elevated in patients admitted to the intensive/medium care unit (median value 44.4 ng/ml, interquartile range 13.6-105.9 ng/ml) and in patients referred to the ward (median value 14.2 ng/ml, interquartile range 7.01-25.1 ng/ml). In addition, PTX3 was associated with duration of hospital stay and acute congestive heart failure. The levels were predictive for bloodstream infection (AUC = 0.71; 95% CI 0.62-0.81). Conclusions: PTX3 may be a useful marker for differentiation of patients with severe disease in patients presenting with fever to the emergency department. (C) 2009 The British Infection Society. Published by Elsevier Ltd. All rights reserved

We present a case of a 53-year-old woman who presented to the emergency room with acute abdominal pain, fever and haemodynamic and respiratory instability and was admitted to the intensive care unit with fulminant septic shock with multiorgan failure. CT imaging of the abdomen showed no gross abnormalities, initial laboratory results are presented in table 1. View this table: Table 1 Laboratory test results Despite adequate resuscitation, broad-spectrum antibiotics and supportive care, following the International Guidelines of the Surviving Sepsis Campaign, she died within a couple of hours. The patient had a history of systemic lupus erythematosus (SLE) with arthralgia, positive antinuclear antibodies and persistently high anti-DNA antibodies, but without active disease and no immunosuppressive medication since years. Leucocyte typing of the initial peripheral blood smear showed Howell-Jolly bodies and diplococci, indicating massive …