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Background The rate of antiphospholipid antibody (aPL) negativization in antiphospholipid syndrome (APS) patients is uncertain, but it is estimated to be as high as 8%. Currently, a consensus definition of aPL negativization is lacking, as well as international recommendations on how to approach treatment in patients with a persistent aPL-negative seroconversion. Aim The aim of the Delphi survey was to evaluate the clinical approach and level of consensus among experts from the APS Study Group of the Italian Society for Rheumatology (SIR-APS) in different clinical scenarios. Methods Experts of SIR-APS were contacted using a survey methodology. Results A structured survey was circulated among 30 experts. Up to 90% of the interviewed experts agreed on defining aPL negativization as the presence of two negative determinations, 1 year apart (90%). Almost full consensus exists among experts in some clinical settings, including: (1) the role of aPL negativization in the management of a thrombotic event determined by concomitant presence of cardiovascular risk factors, both modifiable and not modifiable (90%); (2) approach to young patients with triple aPL positivity who experienced pulmonary arterial thrombotic events and tested negative for aPL detection after 5 years of vitamin K antagonist (VKA) treatment (90%); (3) the use of “extra criteria” aPL antibody testing before pondering VKA suspension (93%). Conclusion A substantial agreement exists among experts on how to define aPL negativization. VKA suspension should be embraced with extreme caution, particularly in case of previous thrombotic events and/or triple aPL positivity. Nevertheless, VKA cessation might be considered when risk factors are carefully monitored/treated and the presence of “extra criteria” aPL is ruled out.

Objectives To demonstrate that unsuccessful treatment optimization in early disease is associated with difficult-to-treat RA (D2T-RA). Methods In this retrospective multicentre cohort study conducted from 09/2021–03/2022, we enrolled individuals fulfilling the 2010 ACR/EULAR RA criteria diagnosed 2000–2019. The outcome was D2T-RA by the EULAR definition. We used robust regression to examine the associations with delay, dose, duration of methotrexate and discontinuation of glucocorticoids. We tested through multinomial regression which factors were associated with persistent inflammatory refractory RA (PIRRA) or non-inflammatory refractory RA (NIRRA). Sensitivity analysis included a case-control study matching the year of diagnosis. Results We enrolled 48 D2T-RA patients and 145 non-D2T-RA controls. Methotrexate was started within 3 months in 16.7% of D2T-RA vs 33.1% of non-D2T-RA (P = 0.011). Adequate duration of methotrexate was obtained in significantly fewer D2T-RA patients (70.8% vs 85.5%). Glucocorticoids were continued beyond 6 months in a higher proportion of D2T-RA patients (70.8% vs 33.8%, P Conclusion Failure to start methotrexate within 3 months and not being off glucocorticoids within 6 months are early predictive features of D2T-RA.

Aim. To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. Methods. All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (

Objective The withdrawal of oral anticoagulation (OAC) in patients with SLE and secondary aPL syndrome (SAPS) who become seronegative has not been clearly investigated to date. Our aim was to evaluate the prevalence of aPL seroconversion and the prognosis of SLE patients with SAPS who withdrew OAC after aPL negativization. Methods We retrospectively analysed data of all SLE patients (ACR criteria) with SAPS (Sydney criteria) prospectively followed-up in our clinic. aPL seroconversion was defined as negativization of lupus anticoagulant, aCL, and anti-β2glycoprotein-1 antibodies on two or more consecutive measurements, at least 12 weeks apart. OAC discontinuation was defined as the definitive withdrawal of all anticoagulants. Results Fifty-five out of 513 (10.7%) SLE patients had vascular SAPS. Sixteen patients (29.1%) became aPL seronegative during follow-up. Immunosuppressive therapy predicted aPL negativization (odds ratio 5.211, 95%CI 1.341, 20.243), whereas APS diagnosis prior to that of SLE (odds ratio 0.078, 95%CI 0.008, 0.799) and triple-positive profile (odds ratio 0.264, 95%CI 0.115, 0.609) were negative predictors of aPL negativization. OAC was discontinued in 13/55 patients (23.6%), after a median follow-up of 45 months (range 1–276) from aPL seroconversion. SLE-related modifiable risk factors for thrombosis were observed in 10/13 patients (77%) at the time of the thrombotic event. No thrombotic recurrences were observed during a mean follow-up time of 44 (19) months from OAC discontinuation. Conclusions Our results suggest that OAC can be safely discontinued in SLE patients who became persistently seronegative for aPL, at least when aPL-related thrombotic events occurred in presence of other thrombotic risk factors.

ObjectiveIt is still a matter of debate whether low-dose acetylsalicylic acid (LDASA) should be prescribed to all patients with SLE during pregnancy. This study aimed at investigating the impact of LDASA on pregnancy outcomes in patients with SLE without history of renal involvement and without antiphospholipid antibodies (aPL).MethodsThis is a retrospective analysis of prospectively monitored pregnancies at seven rheumatology centres. Previous/current renal involvement and aPL positivity were the exclusion criteria. Adverse pregnancy outcome (APO) is the composite outcome of the study and included proteinuric pre-eclampsia, preterm delivery Results216 pregnancies in 187 patients were included; 82 pregnancies (38.0%) were exposed to LDASA treatment. No differences in terms of age at conception, disease duration, clinical manifestations, comorbidities and disease flare during pregnancy were observed between patients taking LDASA and those who did not take LDASA during pregnancy. APO was observed in 65 cases (30.1%), including 13 cases (6.1%) of pre-eclampsia. The incidence of all complications was similar in the two groups. However, it is interesting to note that pre-eclampsia had lower frequency in patients taking LDASA versus those not taking LDASA (2.4% vs 8.3%, p=0.14).ConclusionsIn pregnant patients with SLE without renal involvement and were aPL-negative, there is a low risk of severe obstetric complications, such as early pre-eclampsia. LDASA treatment does not provide a statistically significant advantage over these complications. However, a careful individual risk–benefit balance is warranted.

The concern about the offspring’s health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children.

Objectives The specific roles of remission status, lupus low disease activity state (LLDAS), and damage accrual on the prognosis of pregnancies in women with SLE are unknown. We analysed their impact on maternal flares and adverse pregnancy outcomes (APOs). Methods We evaluated all women (≥18 years) with SLE enrolled in the prospective GR2 study with an ongoing singleton pregnancy at 12 weeks (one pregnancy/woman). Several sets of criteria were used to define remission, disease activity and damage. APOs included: foetal/neonatal death, placental insufficiency with preterm delivery and small-for-gestational-age birth weight. First trimester maternal and disease features were tested as predictors of maternal flares and APOs. Results The study included 238 women (98.3% on hydroxychloroquine (HCQ)) with 230 live births. Thirty-five (14.7%) patients had at least one flare during the second/third trimester. At least one APOs occurred in 34 (14.3%) women. Hypocomplementemia in the first trimester was the only factor associated with maternal flares later in pregnancy (P=0.02), while several factors were associated with APOs. In the logistic regression models, damage by SLICC-Damage Index [odds ratio (OR) 1.8, 95% CI: 1.1, 2.9 for model 1 and OR 1.7, 95% CI: 1.1, 2.8 for model 2] and lupus anticoagulant (LA, OR 4.2, 95% CI: 1.8, 9.7 for model 1; OR 3.7, 95% CI: 1.6, 8.7 for model 2) were significantly associated with APOs. Conclusion LA and damage at conception were predictors of APOs, and hypocomplementemia in the first trimester was associated with maternal flares later in pregnancy in this cohort of pregnant patients mostly with well-controlled SLE treated with HCQ. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT02450396.

Introduction: Systemic Lupus Erythematosus (SLE) is a chronic B cell-mediated autoimmune disease which can potentially involve several organs and systems. The development of SLE is associated with ...

Objectives To derive and validate a definition of low disease activity (LDA) for SLE based on the SLE Disease Activity Score (SLE-DAS), in a real-life multicentre cohort of SLE patients. Methods Derivation was conducted using data from a monocentric cohort of SLE (Portugal), and validation was performed in a multicentre cohort (Italy, France and Spain). The Lupus Low Disease Activity State (LLDAS) was used as comparator. We applied receiver operating characteristics curve analysis against the LLDAS to determine the cut-off of SLE-DAS for LDA using bootstrap methodology. In a second step, we tested a definition of SLE-DAS LDA that included: (i) the statistically derived SLE-DAS upper threshold for LDA and (ii) prednisone dose ≤7.5 mg/day. In the multicentre validation cohort, we assessed the classification performance of this SLE-DAS LDA definition. Results We included 774 patients, 300 in the derivation and 474 in the validation cohort. In the derivation cohort, the optimal cut-off to identify patients in LLDAS was SLE-DAS ≤2.48, presenting an area under the curve of 0.965 (95% CI 0.935, 0.994). When applied to the multicentre validation cohort, the SLE-DAS LDA definition showed a sensitivity of 97.1% and a specificity of 97.7% for LLDAS and an almost perfect agreement (Cohen’s Kappa = 0.933; P Conclusion The SLE-DAS LDA is a validated, accurate and easy-to-use definition for classifying SLE patients in LDA state.

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

ObjectivesThere is an unmet need for accurate and user-friendly definitions of systemic lupus erythematosus (SLE) disease activity and remission. We aimed to derive and validate the SLE Disease Activity Score (SLE-DAS) definitions for disease activity categories and clinical remission state.MethodsDerivation was conducted at Padova Lupus Clinic (Italy). Validation was prospectively performed at Cochin Lupus Clinic (France) and by post hoc analysis of BLISS-76 trial. At each clinic, an expert classified patients in three categories: remission, mild or moderate/severe activity. The SLE-DAS cut-offs were derived using the receiver operating characteristic curve analysis in Padova cohort; its performance was assessed against expert classification in Cochin cohort and British Isles Lupus Assessment Group (BILAG) index in BLISS-76. Gold standard for clinical remission state was the fulfilment of Definition Of Remission In SLE. A Boolean and an index-based definitions of remission were sustained by chi-square automatic interaction detection algorithm. An SLE-DAS online calculator was developed and tested.ResultsWe included 1190 patients with SLE: 221 in the derivation cohort and 969 in the validation cohorts (150 from Cochin; 819 from BLISS-76). Derived cut-offs were: remission, SLE-DAS ≤2.08; mild activity, 2.087.64. Regarding validation in Cochin cohort, sensitivity and specificity are above 90%, 82% and 95% for remission, mild and moderate/severe activity, respectively. The SLE-DAS Boolean-based and index-based remission showed sensitivity of 100% and specificity above 97%.ConclusionThe SLE-DAS is an accurate and easy-to-use tool for defining SLE clinical remission state and disease activity categories, validated against expert assessment and BILAG.

Objectives To determine whether disease remission or low disease activity state at the beginning of pregnancy in SLE patients is associated with better pregnancy outcome. Methods Pregnancies in SLE patients prospectively monitored by pregnancy clinics at four rheumatology centres were enrolled. Patient demographics and clinical information were collected at baseline (pregnancy visit before 8 weeks of gestation) including whether patients were in remission according to the Definition of Remission in SLE (DORIS) criteria and and/or Lupus Low Disease Activity State (LLDAS). Univariate and multivariate analysis were performed to determine predictors of disease flare and adverse pregnancy outcomes (APOs) including preeclampsia, preterm delivery, small for gestational age infant, intrauterine growth restriction and intrauterine fetal death. Results A total of 347 pregnancies were observed in 281 SLE patients. Excluding early pregnancy losses, 212 pregnancies (69.7%) occurred in patients who were in remission at baseline, 33 (10.9%) in patients in LLDAS, and the remainder in active patients. Seventy-three flares (24%) were observed during pregnancy or puerperium, and 105 (34.5%) APOs occurred. Multivariate analysis revealed that patients in disease remission or taking HCQ were less likely to have disease flare, while a history of LN increased the risk. The risk of APOs was increased in patients with shorter disease duration, while being on HCQ resulted a protective variable. An almost significant association between complete remission and a decreased risk of APOs was observed. Conclusions Prenatal planning with a firm treat-to-target goal of disease remission is an important strategy to reduce the risk of disease flares and severe obstetric complications in SLE pregnancies.

Background/Purpose Systemic lupus erythematosus (SLE) is an autoimmune disease, mostly affecting women during their childbearing age. Disease remission before conception is pivotal for a favorable pregnancy outcome. The aims of our study were: 1)to evaluate maternal and fetal complications in a cohort of pregnant SLE patients; 2)to compare Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) in the 6 months before conception as predictors of maternal/fetal complications. Methods All SLE pregnancies were prospectively included until August 2019 at our Unit (Rheumatology Department, University of Padova). All women were monthly followed throughout gestation and at least in one occasion in the 6 months before conception. Disease activity was assessed before pregnancy by SLEDAI-2k and SLEDAS. During gestation, we evaluated SLE activity by the Systemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI) and the SLEDAS index adapted to pregnancy (SLEPDAS). At conception, we considered ‘active’:1)patients with a SLEDAS>2.08; 2)clinically active patients according SLEDAI-2k treated with ≥5 mg/day of prednisone (immunosuppressants and antimalarials were allowed). Statistics were performed with SPSS (V.24.0). Results We enrolled 115 pregnancies in 76 patients (table 1). We found 29 (25.2%) pregnancies with at least one maternal complication and 39 (33.9%) with at least 1 fetal adverse outcome. Positive anti-dsDNA and active disease according SLEDAS (SLEDAS>2.08) at conception resulted to be predictors of maternal complications (p=0.036, OR=2.71, CI 95% 1.07–6.87; p=0.008, OR=4.46, CI 95% 1.48–13.49, respectively). Conversely, active disease according SLEDAI-2k did not result predictive of maternal complications (p=0.255, OR=2.16, CI 95% 9.57–8.16). No predictors of fetal complications were observed. Conclusions SLE-DAS>2.08 and positive anti-dsDNA are risk factors of maternal complications while active SLE according to SLEDAI-2k does not seem to be a predictor of such complications.

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.

Background:Treatment of systemic lupus erythematosus (SLE) is tailored according to the intensity of SLE disease activity and aims to achieve remission. Current definitions of remission and disease activity categories are mostly based on the SLE Disease Activity Index (SLEDAI), which has important limitations. The SLE Disease Activity Score (SLE-DAS) is a validated continuous disease activity score with higher accuracy in measuring SLE activity and higher sensitivity-to-change as compared to SLEDAI1. SLE-DAS is user-friendly with its online calculator.Objectives:To derive and validate the SLE-DAS cut-off values for defining SLE disease activity categories and SLE clinical remission state.Methods:Derivation study was conducted at the Padova Lupus Clinic. Validation was performed prospectively in patients from the Cochin Lupus Clinic and by post-hoc analysis of BLISS-76 (NCT00410384) trial. Gold-standard for clinical remission state was fulfillment of Definition Of Remission In SLE (DORIS). In Padova and Cochin Clinics, at time of inclusion, a senior clinician classified each patient as presenting: (i) remission, (ii) mild, or (iii) moderate/severe disease activity. Derivation of the SLE-DAS cut-offs for disease activity categories was performed using ROC curve analysis against this expert clinical classification. Performance of these SLE-DAS categories of disease activity was assessed as compared with: (i) expert classification (in Cochin cohort); (ii) British Isles Lupus Assessment Group (BILAG) index (in BLISS-76). An index-based and a Boolean definition of remission were tested applying decision trees, using CHAID (chi-square automatic interaction detection) algorithm and their performance estimated.Results:We included 1190 SLE patients (221 in Padova, 150 in Cochin and 819 from BLISS-76 cohorts). In the derivation cohort, best SLE-DAS cut-off values for disease activity categories were: (i) remission, SLE-DAS≤2.08; (ii) mild activity, 2.087.10. Table 1 shows the performance of these SLE-DAS cut-offs. The SLE-DAS Boolean-based definition of remission (all SLE-DAS clinical items scores = 0 and prednisone ≤5mg/day) showed sensitivity and specificity of 100% in the derivation (Padova) and validation (Cochin) clinical cohorts. The SLE-DAS index-based definition of remission (SLE-DAS ≤2.08 and prednisone ≤5mg/day) presented sensitivity =100% and specificity =97.4% in the derivation and validation clinical cohorts. The SLE-DAS definitions of remission were fully substantiated by CHAID.Table 1.Performance of SLE-DAS cut-offs for remission and disease activity categories compared to physician’s classification and BILAG (n =1190).Disease activity categorySensitivity (%)Specificity (%)Accuracy (%)DerivationPadova CohortRemission(SLE-DAS≤2.08)99.397.198.6Mild Disease Activity(2.0874.298.995.5Moderate and Severe Disease Activity(SLE-DAS>7.10)97.496.796.8ValidationCochin CohortRemission(SLE-DAS≤2.08)99.193.998.0Mild Disease Activity(2.0882.699.296.7Moderate and Severe Disease Activity(SLE-DAS>7.10)100.098.698.7ValidationBLISS-76Remission and Mild Disease Activity§vs. Moderate and Severe Disease Activity§§ (SLE-DAS≤7.10 vs. >7.10)91.484.190.8§ Remission/Mild: No BILAG B or A scores§§ Moderate/severe: ≥1 BILAG B or A scoresConclusion:The SLE-DAS is an accurate and easy to use tool for defining clinical remission state and SLE disease activity categories, validated with both the expert assessment and BILAG.References:[1]Jesus D, et al. Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis 2019;78:365-71.Acknowledgements:The authors would like to thank GlaxoSmithKline (Uxbridge, UK) for granting access to the data from the BLISS-76 trial through the Clinical Study Data Request consortium.Disclosure of Interests:None declared

Introduction Les taux des fractions C3 et C4 du complement, comme d’autres proteines, augmentent au cours la grossesse, y compris chez les patientes atteintes de lupus systemique. Alors que la consommation de ces fractions est prise en compte dans les scores d’activite dont le SLE-Pregnancy Disease Activity (SLEPDAI) [1] , leurs valeurs attendues restent inconnues. Notre objectif etait de decrire les variations des taux seriques du C3 et du C4 dans une cohorte prospective de grossesse chez des patientes lupiques. Patients et methodes Les criteres d’inclusion etaient : – Grossesse incluse dans l’etude prospective observationnelle francaise sur les grossesses et les maladies auto-immunes rares (GR2) ; – Chez des patientes ayant un lupus systemique (criteres SLICC) ; – Grossesse terminee avant le 25 decembre 2020. Pour les femmes ayant plus d’une grossesse incluse dans l’etude, seule la 1ere repondant aux criteres d’inclusion a ete analysee. En cas de mesures multiples des fractions C3 et C4 par patiente, seule la premiere mesure de chaque trimestre a ete prise en compte. Resultats 290 grossesses lupiques ont ete analysees. L’âge moyen des femmes etait 32,2 ± 4,7 ans. 669 valeurs de C3 et 648 valeurs de C4 etaient disponibles. La valeur moyenne de la fraction C3 etait de 0,97 g/L au 1er trimestre, 1,10 g/L au second et 1,24 g/L au 3e trimestre, correspondant a une augmentation de 28 % sur l’ensemble de la grossesse. La valeur moyenne de la fraction C4 etait de 0,18 g/L au 1er trimestre, 0,20 g/L au second et 0,20 g/L au 3e trimestre, correspondant a une augmentation globale de 11 %. En analysant uniquement les patientes avec au moins une valeur disponible a chaque trimestre (n = 96 et n = 101, respectivement), nous avons trouve des resultats tres similaires. Ce meme profil evolutif etait retrouve apres exclusion des patientes ayant fait une poussee de lupus au cours de la grossesse (donnees non presentees). Conclusion Dans cette cohorte prospective de 290 grossesses, la fraction C3 augmente de 28 % et la fraction C4 de 11 % entre le premier et le troisieme trimestre. Ces resultats preliminaires permettront de definir plus precisement le seuil inferieur des valeurs normales du C3 et du C4 selon le trimestre de grossesse, et ainsi renseigner de maniere precise les scores d’activite du lupus chez les patientes enceintes.

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients ’ and clinicians’ unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union’s Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. ii) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; iii) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients ’ preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations.

Background Patients with Systemic Lupus Erythematosus (SLE) are often treated with prolonged maintenance therapy with immunosuppressants (ISs) after remission achievement, with the aim of avoiding disease flares and subsequent organ damage. Data on the risk of flare after IS discontinuation and the effect of IS discontinuation on damage accrual are scanty. Objectives Our aims were to analyze damage progression in remitted SLE patients who did or did not discontinued ISs, to assess flare rate after IS withdrawal and to compare damage accrual in patients who did or did not flare after IS discontinuation. Methods We considered all SLE patients included in our lupus database, diagnosed between 1990 and 2018 (ACR criteria), treated with immunosuppressants over their disease course, who discontinued IS due to remission. IS discontinuation was defined as complete withdrawal of any immunosuppressive drug, and remission as clinical SLE Disease Activity Index (SLEDAI)-2K=0. Flares were defined according to SLEDAI Flare Index, and damage according to SLICC damage Index (SDI). Results Eligible patients ever treated with ISs were 319 out of 456 (69.9%) currently in follow-up. Remission lasting at least 6 months was achieved by 206 patients treated with IS (64.6%) (Table 1); among them 105 (51%) discontinued ISs during the follow-up. Mean±SD follow-up after IS withdrawal was 91±71 months (range 6-372). No difference in damage accrual between remitted patients who discontinued or did not discontinue ISs was observed at the end of follow-up, after adjusting for disease duration: median (range) SDI 1 (0-6) and 0 (0-4), respectively. Accordingly, the proportion of remitted patients who accrued damage during the follow-up was similar between those who did or did not discontinue ISs (55% vs. 48%). Among patients who discontinued ISs, 26 (24.7%) experienced a flare after a median (range) of 57 (6-264) months from IS discontinuation. Flares were severe in 50% of cases (Table 2). No difference in damage progression between patients who flared and did not flare after IS withdrawal was found at the end of follow-up: median (range) SDI 1 (0-5) and 1 (0-6), respectively. Moreover, the proportion of patients with damage accrual was similar among patients with and without flare after IS discontinuation (56% vs. 54%). Conclusion In our SLE cohort, the withdrawal of IS therapy in remitted patients did not seem to influence damage progression in the medium-term. Disclosure of Interests: None declared

Background: The treat-to-target strategy in Systemic Lupus Erythematosus (SLE) aims to achieve remission. However, to define a target based on the SLE Disease Activity Index (SLEDAI) is questionable, due to its limitations (especially its dichotomous nature). The SLE Disease Activity Score (SLE-DAS) is a recently validated continuous disease activity score which has a higher accuracy in measuring SLE activity and a higher sensitivity-to-change compared to SLEDAI.1 Objectives: To assess the ability of SLE-DAS to define SLE remission and other disease activity states. Methods: Cross-sectional study of SLE patients fulfilling the ACR’97 and/or SLICC’12 classification criteria and followed at the Padua Lupus Clinic from March to June 2018. At each outpatient visit, the attending clinician scored SLE disease activity (in the last 30 days) using Physician Global Assessment (PGA) (0-3 points, 10 cm scale), SLEDAI-2K and SLE-DAS. A senior rheumatologist expert in SLE, blinded to the disease activity scores, classified each patient in 1 of 4 categories: (i) remission, (ii) low disease activity (LDA), (iii) mild disease activity and (iv) moderate/severe disease activity. The best cut-off values of SLE-DAS to define these categories were estimated using Receiver Operating Characteristic (ROC) curve analysis. Accuracy, precision, sensitivity and specificity values for these cut-off values were then calculated. The agreement between the SLE-DAS and physician’s classification was measured using Kappa coefficient. Statistical significance was set at 0.05. Results: We included 221 patients (84.2% female, mean age of 45.4±13.5 years, mean disease duration of 15.4±9.5 years). In this preliminary study, the proposed cut-off values of SLE-DAS to define each disease activity category were: remission SLE-DAS≤2.08, LDA 2.08 7.64 for (Table 1). The overall accuracy of these SLE-DAS cut-off values to identify each disease activity state was 96.4%. The agreement between SLE-DAS and physician’s classification was very high (k=0.925, p According to the SLE-DAS cut-offs, 68.8% of the patients were in remission, 2.3% in LDA, 10.9% in mild disease activity and 18.1% in moderate/severe disease activity. Conclusion: The SLE-DAS has a high precision in identifying remission, LDA, and other disease activity states in SLE. These results suggest that the SLE-DAS is an accurate tool in defining achievable targets in SLE management. References: [1] Jesus D, Matos A, Henriques C, et al. Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis 2019, Epub ahead of print 9 January 2019. DOI: 10.1136/annrheumdis-2018-214502. Disclosure of Interests: None declared

Objectives Patients with SLE are often exposed to prolonged immunosuppression since few data on flare recurrence in remitted patients who discontinued immunosuppressants are available. We aimed to assess the rate and predictors of flare after immunosuppressant withdrawal in SLE patients in remission. Methods SLE patients diagnosed between 1990 and 2018 (according to the ACR criteria), ever treated with immunosuppressants and currently in follow-up were considered. Immunosuppressant discontinuation was defined as complete withdrawal of any immunosuppressive drug. Reasons for discontinuation were remission, defined as clinical SLEDAI-2K = 0 on a stable immunosuppressive and/or antimalarial therapy and/or on prednisone ⩽5 mg/day, or poor adherence/intolerance. Flares were defined according to the SLEDAI Flare Index. Predictors of a subsequent flare were analysed by multivariate logistic regression. Results There were 319 eligible patients out of 456 (69.9%). Of the 319 patients, 139 (43.5%) discontinued immunosuppressants, 105 (75.5%) due to remission, 34 (24.5%) due to poor adherence/intolerance. The mean (s.d.) follow-up time after immunosuppressant withdrawal was 91 (71) months (range 6–372). Among the patients who discontinued immunosuppressants, 26/105 remitted (24.7%) and 23/34 unremitted patients (67.6%) experienced a flare (P < 0.001) after a median (range) follow-up of 57 (6–264) and 8 months (1–72), respectively (P = 0.009). In patients who discontinued immunosuppressants due to remission, maintenance therapy with antimalarials (OR 0.243, 95% CI 0.070, 0.842) and the duration of remission at immunosuppressant discontinuation (OR 0.870, 0.824–0.996) were independent protective factors against disease flare. Conclusion SLE flares are not uncommon after immunosuppressant discontinuation, even in remitted patients; however, antimalarial therapy and durable remission can significantly reduce the risk of flare.

Background Patients with Systemic Lupus Erythematosus (SLE) are often exposed to prolonged treatment with immunosuppressants (IS). Remission of disease activity should conceptually enable IS withdrawal, but no enough evidence is available regarding the benefits of IS discontinuation, especially in non-renal SLE, or the risk of a subsequent flare. Our aims were to assess the rate of IS withdrawal in SLE remitted patients and the predictors of a subsequent flare and flare-free survival; moreover, to evaluate the effect of IS withdrawal on damage accrual. Methods We studied patients diagnosed with SLE between 1990 and 2018 treated with IS over their disease course who discontinued ISs. IS discontinuation was defined as complete withdrawal of any IS. Reasons for discontinuation were: remission, defined as clinical SLE Disease Activity Index (SLEDAI)−2K=0, or poor compliance/intolerance. Flares were defined according to SLEDAI Flare Index. Predictors of a subsequent flare and flare-free survival were analyzed by multivariate logistic regression and Cox regression analysis, respectively. Results Eligible patients ever treated with IS were 319 out of 456. 139 patients discontinued ISs, 105 of them (75.5%) due to remission. Mean ±SD follow-up after IS withdrawal was 91±71 months (range 6–372). 26/105 remitted (24.7%) and 23/34 unremitted patients (67.6%) experienced a flare (p Table 1 reports characteristics of remitted patients, overall and according to flare occurrence after IS discontinuation. At multivariate logistic regression analysis, antimalarial intake (OR, 95% CI 0.103, 0.023–0.452, p=0.003), older age (OR 0.943, 0.892–0.997, p=0.039) and the duration of remission before IS discontinuation (OR 0.943, 0.938–0.996, p=0.025) were independent protective factors against flares after IS discontinuation. Conversely, no predictive factors of a longer time-to-flare were identified by multivariate Cox-regression analysis. Median damage accrual was similar in patients who discontinued (1, range 0–8) or not IS (1, range 0–9) after adjusting for age, disease duration and cumulative prednisone dose. We separately analyzed data of non-renal remitted patients (37 patients, 35.2%). The only variable associated with a lower flare rate was antimalarial intake (OR 0.048, 0.005–0.503, p=0.002). Conclusions In our cohort, one third of patients treated with IS discontinued the drug during the follow-up, in most cases due to remission. The use of antimalarials after IS discontinuation was independently associated with a significant decrease in the risk of flare. Funding Source(s): None Table 1 reports characteristics of remitted patients, overall and according to flare occurrence after IS discontinuation.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ, This article has been corrected since it first published. The authors would like to notify that title of the article has been changed to:Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines. RMD Open 2019;5:e000784corr1. doi:10.1136/rmdopen-2018-000784cor, Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients’ and clinicians’ unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union’s Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. iii) IVIG is a treatment of resistantDM that may be also used in other resistant-IIMs; iv) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients’ preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations., This publication was funded by the European Union’s Health Programme (2014-2020), Framework Partnership Agreement number: 739531 – ERN ReCONNET. The content of this publication represents the views of the authors only and it is their sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.

Systemic lupus erythematosus (SLE) is a very complex disease where multiple immunological pathways can concur in inducing tissue damage. Cytokines are key mediators in this process and among them the role of interleukin (IL)-12 and the IL-23/Th17 axis has recently emerged. IL-12 and IL-23 have a heterodimeric structure with a common subunit, named p40. Although they share a partially common structure, their functions appear slightly different. Indeed, IL-12 is a key cytokine in inducing an efficient T helper 1 (Th1) response and in Th differentiation, while IL-23 plays a crucial role in chronic inflammation and Th17 cell activation, which results in IL-17 secretion. The increasing knowledge on the interaction between IL-12 and IL-23/Th17 axis in the development of autoimmune diseases has led to the identification of new therapeutic strategies targeting these immunological pathways. IL-23/Th17 axis has recently been suggested to be essential in developing lupus nephritis, both in mice and in humans. In keeping with these observations, ustekinumab, a fully human IgG1κ monoclonal antibody (mAb) directed towards p40 subunit, has been investigated in SLE. Promising data from a phase II randomized controlled trial in SLE patients suggest that this mAb might be a potential novel therapeutic strategy in SLE. In this review, we summarize the complex interaction between IL-12 and IL-23/Th17 axis in SLE with a special focus on drugs which affect this immune pathway. Impact statement Our article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.

Objective The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. Methods We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18–55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). Results At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A “Disease Knowledge Index” (DKI) was created to investigate the degree of patients’ information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. Conclusion Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.

Objectives The aim was to determine whether assisted reproductive technologies (ARTs) confer additional risk in rheumatic patients (in terms of disease flare and fetal–maternal complications) and whether, if performed, their efficacy is affected by maternal disease. Methods Sixty infertile rheumatic women undergoing 111 ART cycles were included. Clinical pregnancy rate, live birth rate, maternal disease flares and maternal–fetal complications were recorded. Results One hundred and eleven ART cycles in 60 women were analysed. We reported 46 pregnancies (41.4%), 3 (3.1%) cases of ovarian hyperstimulation syndrome and no cases of thrombosis during stimulation, pregnancy and puerperium. One or more maternal complication was reported in 13 (30.2%) pregnancies, and fetal complications occurred in 11 fetuses (21.1%). The live birth rate was 98%, but we reported three (6%) perinatal deaths in the first days of life. During puerperium, we recorded one (2.5%) post-partum haemorrhage and one (2.5%) articular flare. Conclusion The safety and efficacy of the ARTs, demonstrated in the general population, seems to be confirmed also in rheumatic patients. No evidence was found to advise against their application, and the choice of therapy should be made depending on the patient’s risk profile, irrespective of whether the pregnancy is natural or artificial induced.

Pulmonary arterial hypertension (PAH) is a serious complication of connective tissue disorders (CTDs), and CTD-PAH is the second cause of PAH after the idiopathic form. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which can lead to right heart failure and death. About 90% of CTD-PAH cases are associated with systemic sclerosis (SSc, 74%), mixed connective tissue disease (MCTD, 8%) or systemic lupus erythematosus (SLE, 8%). CTD-PAH has also been reported, albeit rarely, in Sjögren syndrome, inflammatory idiopathic myopathies and rheumatoid arthritis. As for idiopathic PAH, the impaired production of vasoactive mediators such as nitric oxide and prostacyclin, and the increased production of vasoconstrictors and proliferative mediators such as endothelin-1, affect the vascular tone and promote vascular remodeling. Moreover, there is growing evidence suggesting that inflammation and autoimmunity may contribute to the genesis and progression of CTD-PAH, especially in SLE and MCTD patients who require an early administration of corticosteroids and immunosuppressants in order to avoid irreversible pathologic changes in pulmonary vessels. Conversely, immunosuppressive agents are ineffective in SSc-PAH, which requires a timely and aggressive treatment with specific PAH therapies (combination therapy). In this review, we summarized the current data on the pathophysiology and treatment of CTD-PAH. Impact statement Our article focuses on the pathogenesis and treatment of CTD-PAH. In the latest ESC/ESR guidelines for PAH, the authors underline that although CTD-PAH should follow the same treatment protocol as idiopathic PAH, the therapeutic approach is more complex and difficult in the former. This review throws light on several peculiar aspects of CTD-PAH and the latest findings in the pathogenesis, namely, the role of inflammation in the maladaptive right ventricle remodeling in SSc-PAH where immunosuppressants are classically believed to be ineffective. Furthermore, we discuss the major critical points in the therapy of CTD-PAH which is one of the strengths of our article. To the best of our knowledge, there are no other reviews that exclusively focus on the pathogenesis and treatment of CTD-PAH patients, with an emphasis on the more critical issues. Thus, it is our contention that our work would be of interest to the readers.

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes. info:eu-repo/semantics/publishedVersion

Background:Active Systemic Lupus Erythematosus (SLE) during pregnancy is associated with poor obstetrical outcome but it is still not clear if remission, lupus low disease activity state (LLDAS) is the best target to achieve at conception. Besides, the effect of damage on pregnancy outcome has not been studied.Objectives:Our aim was to determine the 1st trimester risk factors for adverse pregnancy outcome (APO).Methods:Inclusion criteria were: 1) women≥18 years enrolled in the prospective GR2 study; 2) with SLE (SLICC criteria); 3) and an ongoing singleton pregnancy at 12 weeks (only 1 pregnancy per patient). We used the following definitions: DORIS1, DORIA2, clinical SLEDAI-2K=0, LLDAS3 (for SLE activity), SFI4 (for flares), and SLICC-damage index5 (for damage). APO included: foetal death, neonatal death, placental insufficiency with premature deliveryrd percentile).Results:238 patients were included. 234 (98.3%) women were on hydroxychloroquine (HCQ) and 206 (86.5%) had a clinical SLEDAI-2K=0. Regarding pregnancy outcome, 230 (96.6%) patients had a live birth (mean term 37.7 weeks). Thirty-four (14.3%) patients developed at least 1 APO: placental insufficiency (n=22), foetal death (n=7), neonatal death (n=1), and SGA (n=5). Two different regression logistic models were assessed, one for DORIA and one for LLDAS. We found that only SLICC-Damage index and lupus anticoagulant (LAC) were associated with APO (p=0.02, OR 1.8, 95% CI: 1.1-2.9; p=0.001, OR 4.2, 95% CI: 1.8-9.7 respectively for DORIA model; p=0.03, OR 1.7, 95% CI:1.1-2.8; p=0.002, OR 3.7, 95% CI: 1.6-8.7 respectively for LLDAS model).Conclusion:We confirmed that LAC predicts APO. We found for the first time that chronic damage at 1st trimester also predicted APO. No effect of remission/LLDAS was observed in this cohort of patients on HCQ with a stable and well-controlled SLE.References:[1]van Vollenhoven R, et al. ARD 2017.[2]Zen M, et al. ARD. 2015.[3]Franklyn, K. et al. ARD 2016.[4]Petri M, et al. NEJM 2005.[5]Gladman DD, et al. Arthritis Rheum, 1997.Table 1.Univariate analysis for APOMaternal featuresTotal (N=238)APO (N=34)Non-APO (N=204)P valueAge, mean (SD)31.6(4.5)30.7(4.8)31.7(4.4)0.22Secondary APS34(14.3)10(29.4)24(11.8)0.01Previous renal phenotype67(28.2)13(38.2)54(26.5)0.16At least 1 flare during pregnancy37(15.5)6(17.4)31(15.2)0.80Positive anti-DNA (N=222)104(46.8)21(67.7)83(43.5)0.01Hypocomplementemia (N=216)57(26.4)13(40.6)44(23.9)0.05LAC (N=232)41(17.7)15(44.1)26(13.1)Triple aPL (N=232)17(7.3)5(14.7)12(6.1)0.0824h-proteinuria>0.5g/day9(3.8)3(8.8)6(2.9)0.12Activity/DamageSLEDAI-2K, median (IQR) (N=212)2(0-3)2(2-4)2(0-2)0.01SLICC-DI, median (IQR) (N=236)0(0-0)0(0-0)0(0-0)0.007PGA, median (IQR)(N=235)0.1(0-0.2)0.1(0-0.41)0.1(0-0.2)0.06DORIA remission*154(64.7)17(50.0)137(67.2)0.05DORIS remission**147(61.8)17(50.0)130(63.4)0.13LLDAS (N=219)157(71.7)19(57.6)138(74.2)0.05Clinical SLEDAI-2K=0206(86.5)28(82.4)178(87.3)0.44TreatmentPrednisone (PDN)119(50.0)23(67.7)96(47.1)0.03PDN (mg/day) median (IQR)7(5-10)0(0-6)5(0-10)0.007Immunosuppressants57(24.0)13(38.2)44(21.6)0.04Hydroxychloroquine234(98.3)34(100.0)200(98.0)1.00Low dose aspirin165(69.3)29(85.3)136(66.7)0.03Low molecular weight heparin61(25.6)15(44.1)46(22.6)0.01Legend: APS: antiphospholipid syndrome; aPL: antiphospholipid; PGA: Physician global assessment. *: DORIA definition of remission = clinical SLEDAI=0 and prednisone ≤5 mg/day; **: DORIS definition of remission = clinical SLEDAI=0, prednisone ≤5 mg/day, and PGADisclosure of Interests:None declared.

Objective To investigate effectiveness and safety of belimumab in patients with active systemic lupus erythematosus (SLE) in a clinical practice setting. Methods Sixty-seven patients with active SLE, mean ± SD age 39.3 ± 10.2 years, from 2 Italian prospective cohorts were treated with belimumab (10 mg/kg on day 0, 14, 28, and then every 28 days) added to background therapy. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, the Disease Activity Score in 28 joints (DAS28), 24-hour proteinuria, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score, anti–double-stranded DNA (anti-dsDNA), C3 and C4 levels, and prednisone daily dose were recorded at baseline, month 3, 6, 9, 12, 18, and 24. Arthritis was subdivided into “classical” (CLP) and “rheumatoid-like”; skin manifestations into acute (ACLE), subacute (SCLE), and chronic. SLE flares, defined according to the SLEDAI Flare Index, were calculated before and after belimumab initiation. Adverse events were carefully evaluated during treatment. Statistics were performed by the SPSS package (version 21.0). Results Mean ± SD followup was 16.2 ± 9.5 months. Main refractory manifestations treated with belimumab were musculoskeletal (37.3%), mucocutaneous (22.4%), and renal (23.9%). SLEDAI-2K, prednisone daily dose, anti-dsDNA, DAS28, CLASI, and 24-hour proteinuria decreased during treatment. DAS28 score decreased in patients with polyarthritis (P

Background Whether patients with autoimmune rheumatic diseases (ARD) have a higher risk for SARS-CoV-2 infection (COVID-19) and how SARS-CoV-2 pandemic impacts on adherence to therapy has not been fully elucidated. We assessed the rate and clinical presentation of COVID-19, and adherence to therapy in a large cohort of patients with ARD followed-up in a tertiary University-Hospital in Northeast Italy. Methods Between April 9th and April 25th, 2020, after SARS-CoV-2 infection peak, a telephone survey investigating the impact of COVID-19 on patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), and idiopathic inflammatory myopathies (IIM) was administered. Demographics, disease activity status, therapy, occupational exposure, and adherence to social distancing advise were also collected. Results 916 patients (397 SLE, 182 AAV, 176 SSc, 111 RA, 50 IIM) completed the survey. 148 patients developed at least one symptom compatible with COVID-19 (cough 96, sore throat 64, fever 64, arthromyalgias 59, diarrhea 26, conjunctivitis 18, ageusia/hyposmia, 18). Among the 916 patients, 65 (7.1%) underwent SARS-CoV-2 nasopharyngeal swab (18 symptomatic and 47 asymptomatic), 2 (0.21%) tested positive, a proportion similar to that observed in the general population of the Veneto region. No deaths occurred. 31 patients (3.4%) withdrew ≥1 medication, mainly immunosuppressants or biologics. Adoption of social distancing was observed by 860 patients (93.9%), including 335 (36.6%) who adopted it before official lockdown. Conclusions COVID-19 incidence seems to be similar in our cohort compared to the general population. Adherence to therapy and to social distancing advise was high., Highlights • SARS-CoV-2 infection rate in ARDs seems to be similar to that of the general population. • Adoption of social distancing measures was prevalent among different ARD groups. • Earlier social distancing was more common in unremitted patients, treated with multiple drugs. • Therapy discontinuation due to COVID-related concerns was rare, but undertaken even by active patients. • Therapeutic regimens based on ≥3 drugs were associated with therapy discontinuation in our cohort.

Background:Whether and when immunosuppressive therapy may be safely withdrawn in patients with lupus nephritis (LN) is still poorly defined. Indeed, there is no clear agreement about the optimal duration of maintenance treatment.Objectives:We aimed at assessing the rate and predictors of flare after IS withdrawal in patients with LN in remission.Methods:Patients with systemic lupus erythematosus (SLE) (ACR criteria) and biopsy-proven LN diagnosed between 1990 and 2019, ever treated with IS and currently in follow-up were considered. IS discontinuation was defined as the complete withdrawal of any immunosuppressive drug in patients in remission. Remission was defined as normal serum creatinine, proteinuria 0.5 g/24h requiring an increase in corticosteroid therapy or the reintroduction of IS. Predictors of a subsequent flare were analyzed by multivariate logistic regression analysis.Results:Out of 456 SLE patients regularly followed-up, 206 (45.1%) had LN and were considered in our study. Eighty-three patients (40.3%) discontinued IS after remission achievement (Table 1). After stopping therapy, patients were followed for a mean±SD of 99±77 months (range 12-378). Nineteen patients (22.8%) developed a flare after IS discontinuation, after a mean±SD follow-up of 78±68 months (range 7-312), and were re-treated; among them, 6 patients (7.2%) experienced a renal and 13 (15.6%) an extra-renal flare. Compared to patients who flared, patients in persistent IS-free remission had longer remission before IS withdrawal (51.2±31.5 vs. 29.3±16.5 months, pTable 1.Characteristics of 83 patients with LN in remission who discontinued immunosuppressive therapy, overall and according to flare occurrenceTotal patients (83)Patients with flare (19)Patients without flare (64)P valueFemale, N(%)72 (88.7)16 (84.2)56 (87.5)nsAge at 2019, years43±1139±11.545±10.40.049SLE duration at 2019, years18±916.7±9.018.6±8.6nsSLE duration at IS discontinuation, years9.7±7.67.1±6.110.5±7.8nsTime to achieve remission, months27±3722.1±35.628.5±37.6nsRemission duration at IS discontinuation, months46±3029 ±16.551±31.5IS therapy duration, years6.7±4.35.2±3.87.1±4.20.061Anti dsDNA, N(%)65 (78.3)18 (95)47 (73)0.059HCQ after IS discontinuation, N(%)67 (80.7)12 (63.1)55 (85.9)0.005IS, immunosuppressant; HCQ, hydroxychloroquineTable 2.Multivariate logistic regression: predictors of flare occurrenceDependent variable: flare occurrenceOR95% CIp valueNumber of ISs, ever3.2641.030-10.3420.044HCQ therapy after IS discontinuation0.0960.014-0.6520.017Remission duration at IS discontinuation0.9540.912-0.9970.037Cyclophosphamide, ever0.0650.008-0.5480.012IS, immunosuppressant; HCQ, hydroxychloroquineConclusion:Based on our experience, withdrawal of IS is feasible in selected patients with LN, i.e. patients who achieved stable remission and received maintenance therapy with antimalarials. Patients who experience new flares can re-achieve remission with an appropriate treatment.Disclosure of Interests: :Margherita Zen Speakers bureau: BMS, Ely Lilly, Janssen, GSK, Mariele Gatto Speakers bureau: GSK, Francesco Benvenuti: None declared, Francesca Saccon: None declared, Maddalena Larosa: None declared, Luca Iaccarino Speakers bureau: GSK, Pfizer, Janssen, Novartis, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS

Background:One of the 3 features of obstetrical antiphospholipid syndrome (APS) is severe preeclampsia (PE). Its time of occurrence, the associated risk of thromboses and systemic lupus erythematosus (SLE) have not been reported yet.Objectives:We analyzed severe PE in a series of women with APS.Methods:We retrospectively collected data of female patients from 5 French internal medicine and 1 Italian rheumatology units. Inclusion criteria were: a severe PE/eclampsia(1), that occurred before 34 weeks of gestation (WG) in patients who met the APS classification criteria(2).Results:40 patients were enrolled (Table 1). Because of known APS/positive aPL/previous obstetrical complications, 23(57.5%) patients were treated during the index PE: 4 with low dose aspirin (LDA), 4 with low molecular weight heparin (LMWH), and 15 with a combination of both. 7 patients were also treated with hydroxychloroquine, 8 with corticosteroids and 3 with immunosuppressants. 17(42.5%) patients received no treatment. 24(60%) live births were observed. During a follow-up period of 3 years, 26(65%) patients had at least 1 new pregnancy, with a total of 38 pregnancies which resulted in 33(86.8%) live births. 57.5% pregnancies who resulted in live births occurred without any maternal or fetal complications. All 26 patients who had at least 1 pregnancy after index PE were treated with LDA; LMWH was given at prophylactic and therapeutic dosage in 13(50%) patients, respectively. No patient experienced 3 consecutive miscarriages.Table 1.40 APS patients with severe PEOverall features (n, %)Patients40 (100)Age at PE, (median, IQR)30.5 (27-33)PE term, WG (median, IQR)25.5 (23-29) Live births24 (60) Birth term, WG (median, IQR)25.5 (23.7-30.3) Associated SLE12 (30)Maternal complications (n, %)25 (62.5) HELLP18 (45) E6 (15) CAPS3 (7.5) Placental abruptions3 (7.5)Fetal complications (n, %)31 (77.5) IUGR18 (45) IUFD11 (2.5) Preterm delivery22 (55)Obstetrical history (n, %) Primiparous21 (52.5) Index PE before APS12 (30)Thrombosis (n, %) Thrombosis before PE index14 (35.0) Thrombosis after PE index2 (5.0)Abs at APS diagnosis (n, %) aPL triple positivity21 (52.5) IgG/IgM anti-cardiolipin34 (85.0) IgG/IgM anti-β2GPI25 (62.5) LAC33 (82.5)Legend to Table 1:PE: preeclampsia; APS: antiphospholipid syndrome; IQR: interquartile range; WG: weeks of gestation; SLE: systemic lupus erythematosus; HELLP: Hemolysis, elevated liver enzymes, low platelet; E: eclampsia; CAPS: catastrophic APS; IUGR: intrauterine growth restriction; IUFD: intrauterine fetal death; CHB: congenital atrioventricular block; aPL: antiphospholipid antibodies; LAC: lupus anticoagulant.Conclusion:Among the APS criteria, “3 consecutive miscarriages criterion” was not found. The majority of patients also experienced thrombosis and SLE before the index PE.References:[1]Diagnosis and Management of preeclampsia and eclampsia. International Journal of Gynecology &Obestetrics 2002;77:67-75.[2]Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295e 306.Disclosure of Interests:Maddalena Larosa: None declared, Nathalie Morel: None declared, Meriem BELHOCINE: None declared, Amelia Ruffatti: None declared, Nicolas Martin Silva: None declared, Romain Paul: None declared, Luc Mouthon: None declared, Michel DREYFUS: None declared, Jean-Charles PIETTE: None declared, Odile Souchaud-Debouverie: None declared, Catherine Deneux-Tharaux: None declared, Vassilis Tsatsaris: None declared, Emmanuelle Pannier: None declared, Gaêlle Guettrot Imbert: None declared, Véronique LE GUERN Grant/research support from: UCB for GR2 study (to our institution), Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institution

Background The efficacy of tacrolimus (TAC) in lupus nephritis (LN) has been recently demonstrated in several randomised controlled trials in asian cohorts.1 Nevertheless, data on real-life experience and long-term safety of TAC are still lacking. Objectives To assess efficacy and safety of TAC in SLE patients with refractory LN in a multi-centric prospective cohort. Methods Adult SLE patients with refractory LN from 4 Italian centres were prospectively followed for at least 12 months. Clinical and serological variables and previous/concomitant medications were collected at baseline,3,6,12 months after starting TAC. Renal response was assessed by using EULAR/ERA-EDTA definitions.2 Adverse events (AEs) included non-infectious and infectious AEs; they were defined severe (SAE) when hospitalisation and/or death and/or life-threatening manifestations occurred. Data were analysed using SPSS (v.24.0). Results Thirteen SLE patients (8 females,5 males, mean age 33.7±10.2, mean disease duration 11.9±5.9) were enrolled (table 1). Concomitant medications included: prednisone(100%), mycophenolate mofetil(92.3%), hydroxychloroquine(53.8%), azathioprine(7.7%), belimumab(7.7%) and cyclosporine(7.7%). The average number of previous immunosuppressants taken by each patient was 3.15±1.90. Six-months renal response was achieved by 5/13 patients (38.5%): complete renal response (CRR) in 3 (60.0%) and partial renal response (PRR) in 2 patients (40.0%). Twelve-months renal response occurred in 4/13 patients (30.8%): CRR in 2/13 (50.0%) and PRR in 2/13 (50.0%). One patient achieved CRR at 6 and 12 months; one patient achieved PRR at 6 months and CRR at 12 months. Six patients (46.1%) discontinued TAC after an average follow up period of 10.2±7.8 months. Causes of discontinuation were: 3 non-infectious non-SAEs, 1 flare, 1 non-infectious SAE, and 1 non-response. Concerning AEs, no severe infections or deaths occurred. Conclusions Our preliminary data from clinical practice setting suggest that TAC could be a therapeutic rescue strategy for refractory LN. Further studies are needed to prove TAC efficacy in the long term. References [1] Mok CC, Ying KY, Yim CW, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis2016;75:30e6. [2] Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis2012;0:1–12. Disclosure of Interest None declared

Background Rheumatic Diseases (RD) frequently affect women during reproductive age, therefore counselling on family planning is crucial for their quality of life. Children’s outcome is a major topic, but no large studies are available. Objectives To assess the long-term health conditions of children born to women with RD in a large multicentre cohort. Methods 24 Rheumatology Centres distributed the questionnaire (65 multiple-choice and 12 open-answer questions) to consecutive patients (18–55 years) in September 2015. Data were analysed dividing children upon maternal diagnosis: Chronic Arthritides (CA) and Connective Tissue Diseases (CTD). Results Data were collected for 320 children (166 males, 52%) born to 184 mothers (63 CA and 121 CTD). At the time of interview, children had a mean age of 17.1±9.6 years. Preterm delivery ( Conclusions In this long-term follow-up of children born to mothers with RD in this large, multicenter study of randomly interviewed women each AIID did not display a significantly increased frequency as compared to the literature; only coeliac showed a mild increased frequency. Children with LD had a tendency to cluster in the group of mothers with CTD, especially after maternal diagnosis (4/63, 6.3%), with a higher frequency as compared to general paediatric population. No significant relationships between ND/LD and prematurity, intrauterine drug exposure or maternal autoantibodies were identified. Acknowledgements Statistical analysis supported by an unrestricted grant by UCB Pharma. The authors wish to thank Patients Associations and Participants to the survey. Disclosure of Interest None declared

Background Prolonged treatment with immunosuppressants (IS) has been associated with long-term complications in Systemic Lupus Erythematosus (SLE); however, few data on IS discontinuation in remitted patients are available to date. Objectives We conducted an observational study to describe the proportion of SLE patients who discontinued IS and to assess the potential predictors of a subsequent flare. Methods We used data from Padua Cohort, which includes 454 SLE patients followed up from 1990 to 2017. Patients treated with IS over the disease course who discontinued IS and seen at least once in 2017 were studied. Reasons for discontinuation were: remission (defined by clinical SLE disease activity Index=0) or poor compliance/intolerance. Flares were defined according to SLEDAI Flare Index. Predictors of a subsequent flare were analysed by multivariate logistic regression analysis. Results Eligible patients who were ever treated with IS were 297. IS were discontinued in 106 patients (35.7%): mycophenolate (50, 47.2%), azathioprine (27, 25.5%), cyclophosphamide (11, 10.4%), methotrexate (10, 9.4%), cyclosporine (8, 7.5%). Mean ±SD follow-up duration after IS withdrawal was 82±64 months (range 6–320). 83 out of 106 patients (78.4%) discontinued IS due to remission (mean remission duration at IS discontinuation 39±28 months), and 23 (21.6%) due to poor compliance/intolerance. Among remitted patients, 18 (78.3%) experienced a flare after IS discontinuation (9/55 patients with nephritis, 5/10 with arthritis, 2/9 with skin involvement, 1/3 with neuroSLE, 1/4 with haematological involvement) after a mean of 65±52 months (range 6–180). Conversely, in patients with poor compliance/intolerance, 17 relapsed (73.9%) after a mean of 22±16 months. Flare-free 10 year-survival rate was higher in patients who discontinued IS due to remission than to poor compliance/intolerance (p In patients who discontinued IS due to remission, a shorter duration of remission at IS discontinuation was associated with disease relapse (p=0.006). Patients who were on IS due to nephritis had a lower risk of flare after IS discontinuation compared with patients with other manifestations (16.4% vs 32.1%, OR 0.58, 95% 0.32–0.98, p=0.049); patients with arthritis were those who were more likely to flare (OR 4.61, 95% CI 1.16–18.29, p=0.035). Positive anti-SSA/SSB (OR 0.45, 95% CI 0.26–0.78, p=0.012) and antimalarials intake after IS discontinuation (OR 0.22, 95% CI 0.07–0.73, p=0.015) were associated with a lower risk of flare. No clinical features over the disease course were associated with flare occurrence. At multivariate analysis, antimalarial use was the strongest protective factor against flares after IS discontinuation (OR 0.22, 95% CI 0.05–0.85, p=0.029). Conclusions In our cohort, one third of patients treated with IS discontinued the drug during the follow-up, in most cases due to a prolonged remission. Patients who discontinued IS due to remission had a higher free-survival rate than those who discontinued these drugs due to poor compliance/intolerance. The use of antimalarials after IS discontinuation was independently associated with a significant decrease in the risk of flare. IS discontinuation in patients with arthritis requires particular caution. Disclosure of Interest None declared

Objective To evaluate the prevalence of different definitions of remission and their effect on damage in systemic lupus erythematosus (SLE). Design and method We considered 293 caucasian SLE patients followed-up for 7 years (2009–2015): 253 (86.3%) were female, mean ±SD disease duration 11.1±7.8 years. Disease activity was assessed by clinical SLEDAI-2K (c-SLEDAI) and damage by SLICC/ACR Damage Index (SDI). We evaluate the effect of different definitions of remission (c-SLEDAI=0; c-SLEDAI ≤1; c-SLEDAI=0 and prednisone ≤5 mg/day; c-SLEDAI ≤1 and prednisone ≤5 mg/day; c-SLEDAI=0 and PGA Results Frequency of remission achieved during the 7 year follow-up are reported in table 1 according to the different definitions. The mean increase in SDI and the percentage of patients with increased of SDI from the baseline to the end of follow-up were significantly higher in unremitted and 1 year remitted patients compared with patients with 2-, 3-, 4- and ≥5 year remission, irrespective of the definition of remission. 5 year remitted patients had lower damage compared with 2 year (p Conclusions The inclusion of PGA

Background Rheumatic Diseases (RD) frequently affect women during reproductive age, therefore counselling on family planning is crucial for their quality of life. Children’s outcome is a major topic, but no large studies are available. This study aimed at assessing the long-term health conditions of children born to women with RD. Methods 24 Italian Rheumatology Centres distributed the questionnaire (65 multiple-choice and 12 open-answer questions) to consecutive patients (aged 18–55) during September 2015. Data were analysed dividing children upon maternal diagnosis: Chronic Arthritides (CA) and Connective Tissue Diseases (CTD). Results Data were collected for 320 children born to 184 mothers (63 CA and 121 CTD). At the time of interview, children had a mean age of 17.1±9.6 years. Pre-term delivery ( The occurrence of an autoimmune/inflammatory disease (AIID) and/or neurodevelopmental disorders (ND)/learning disabilities (LD) is reported in table 1. Twelve children (3.7%) were diagnosed with an AIID, mostly coeliac disease (8/12, 67%). Eleven children (3.4%) were diagnosed as having a ND and/or LD by a Paediatric Neuropsychiatrist. Data of in utero exposure to maternal autoantibodies and/or anti-rheumatic drugs were retrieved for 280 children (87.5%) and a comparison was performed between affected (n=11) and not-affected children (n=258). No association was found with ND/LD and in utero exposure to autoantibodies (ANA, anti-Ro, anti-dsDNA, aPL) or drugs (HCQ,AZA or steroids), neither with sex, preterm birth, birth weight or maternal diagnosis. Conclusions The long-term follow-up of children born to mothers with RD did not raise particular concerns in terms of relevant health problems. In particular, each AIID did not display a significantly increased frequency as compared to the literature. Children with ND/LD had a tendency to cluster in the group of mothers with CTD, especially after maternal diagnosis, with a higher frequency as compared to GPP (7.9% vs 3%). Our data suggest that the development of ND/LD in children of patients with RD cannot be linked exclusively to maternal disease. The results of this study can be reassuring for patients with RD about problems in the offspring possibly related to their disease.