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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.

It was with great interest that we read the letter ‘SLE-DAS: Ready for routine use?’ by Mathew and coauthors.1 Mathew et al commented on our recent article reporting the derivation and validation of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS),2 which demonstrated a much higher sensitivity to change of SLE disease activity, as compared with SLE Disease Activity Index 2000 (SLEDAI-2K). Mathew et al ’s main concern is in regard of the SLE-DAS scoring of active lupus nephritis (LN). The SLE-DAS renal component is measured continuously, applying a logarithmic scale of proteinuria absolute value (to be scored only if above 500 mg/day and provided it is attributable to active LN). This is very different of the SLEDAI-2K renal component that comprises four dichotomous variables (proteinuria above 500 mg/day, pyuria, haematuria and urinary casts, each one scored solely as present or absent with a weight of 4 points if present and regardless of severity).3 In the derivation of the SLE-DAS, we modelled the renal component using longitudinal data of real patients with active LN from a large, well-characterised tertiary lupus cohort.4 5 The SLE-DAS with its continuous scoring of the absolute value of proteinuria amends risks of major bias of SLEDAI-2K regarding renal involvement. In patients with active LN, the …

It was with great interest that we read the letter ‘Performance of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) in a Latin American population’.1 Rodriguez-Gonzalez et al commented on our recent manuscript reporting the derivation and validation of Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS),2 which demonstrated a much higher performance to detect clinical meaningful changes of SLE disease activity, as compared with SLE Disease Activity Index 2000 (SLEDAI-2K).3 In their letter, Rodriguez-Gonzalez et al reported a cross-sectional monocentric cohort study of 227 Mexican Mestizo SLE patients, in which they found a very high positive correlation between the SLE-DAS and the SLEDAI-2K (rho=0.92, p

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.

It was with great interest that we read the letter ‘Assessment of responsiveness of the musculoskeletal component of SLE-DAS in an independent cohort’ by Hassan et al .1 We recently published the derivation and validation of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS), a new continuous measure of SLE disease activity with high sensitivity and specificity to change.2 Hassan et al report in their letter that in an analysis of 20 SLE …

Background:Belimumab (BEL) is a monoclonal antibody approved for SLE treatment but few data are available about its use before or during pregnancy.Objectives:Our study aims to describe pregnancies in SLE patients who have discontinued BEL before conception, at positive pregnancy test or during pregnancy.Methods:Data from prospectively-followed pregnancies (2014-2020) in SLE patients treated with BEL in 3 Italian centers where retrospectively collected, focusing on maternal disease activity, obstetric and neonatal outcome. Continuous data are expressed as median [min-max].Results:Thirteen SLE pregnancies were analyzed (median age at conception 32 [24-41] years; 77% spontaneous, 69% primigravidae). All patients had positive ANA and anti-dsDNA antibodies; 4 had anti-Ro antibodies (31%); 4 had anti-phospholipid antibodies (aPL; 1 single, 2 double and 1 triple positivity). Seven patients (54%) had a history of lupus nephritis (LN); 2 patients (15%) had a concomitant diagnosis of antiphospholipid syndrome (1 thrombotic-APS and 1 thrombotic+obstetric-APS).Ten (77%) pregnancies were planned and the use of BEL with regard to pregnancy was agreed with the patient during preconception counseling. At preconception visit, 8 patients were in remission while 5 had active disease (median SLEDAI 3 [0-8]).BEL (11 intravenous, 2 subcutaneous) was stopped in 2 cases before conception, in 7 at positive pregnancy test and in 4 during pregnancy (2 at 11th week, 1 at 22nd, 1 at 24th); median duration of treatment at discontinuation was 29 [4-68] months. Other treatments during pregnancy were: oral prednisone in 12 cases (92%); intravenous methylprednisolone in 1 (8%); hydroxychloroquine in 10 (77%); chloroquine in 1 (8%); azathioprine in 5 (39%); calcineurin inhibitors in 5 (39%); low-dose acetylsalicylic acid in 10 (77%); low molecular weight heparin in 9 (69%).Three flares occurred during the 3rd trimester in patients who stopped BEL at positive pregnancy test.Live-births occurred in 92% of the pregnancies. A patient with thrombotic+obstetric-APS and LN, underwent assisted reproductive technology (embryo donation) and developed eclampsia (25thweek), an urgent cesarean section was performed and the newborn died after 3 days. One pre-eclampsia occurred in a patient with history of LN, double aPL positivity and active disease. One miscarriage at 11th week occurred; no early miscarriages (th week) were recorded. Pregnancy complications and outcomes are reported in Table 1.Table 1.Pregnancy complications and outcomes according to the timing of discontinuation of BEL.BEL STOPPED PRECONCEPTIONALLY(2)BEL STOPPED AT POS PREGNANCY TEST(7)BEL STOPPED DURING PREGNANCY(4)Pre-eclampsia0/20/71/4 (25%)Eclampsia0/20/71/4* (25%)Gestational Diabetes0/21/7 (14%)0/4IUGR0/21/7 (14%)1/4* (25%)pPROM/PROM0/20/71/4 (25%)Live birth1/2 (50%)7/7 (100%)4/4 (100%)Severe pre-term birth(≤ 34thweek)0/20/71/4* (25%)Late pre-term birth(35th- 37thweek)0/23/7 (43%)0/4Small for Gestational age neonate0/24/7 (54%)1/4 (25%)Late miscarriage (>10thweek)1/2 (50%)0/70/4Perinatal death0/20/71/4* (25%)IUGR: IntraUterine Growth Restriction; PROM: Premature Rupture of Membrane; pPROM: pretermPROM; *in the same patient (history of thrombotic and obstetric-APS and lupus nephritis) who underwent Assisted Reproductive Technologies (embryo donation).No malformations were recorded. Two newborns were transferred to the Intensive Care Unit (1 for milk protein intolerance and 1 for desaturation).Eight newborns received vaccinations according to national schedule (missing data for 3). Five newborns were breastfed, 1 received formula milk and 5 mixed-feeding. BEL was resumed in 7/13 patients after pregnancy (in 4 cases for flare), after a median period of 5 [4-22] months.Conclusion:While more data are needed, this small series suggests that BEL might be a therapeutic option for SLE patients during pregnancy planning, similarly to other biological drugs used in chronic forms of arthritis.Disclosure of Interests:None declared

Background:Anti-citrullinated alpha enolase antibodies have been investigated in rheumatoid arthritis and associated with bone erosion and interstitial lung disease but little is known about their prevalence and role in connective tissue diseases (CTDs).Objectives:The aim of this study was to investigate the prevalence and relevance of anti-CEP1 antibodies in CTDs.Methods:Serum samples from five independent patient cohorts were assessed: 1) established (est) primary Sjogren’s syndrome (pSS) N=78, 2) est-systemic lupus erythematosus (SLE) N=52, 3) est-systemic sclerosis (SSc) N=71, 4) pSS at disease onset N=30, 5) SLE at disease onset N=46 (cohorts 4 and 5 had at least 3 years of follow-up). Samples from ninety sex and age matched healthy donors (HD) and 200 patients with est-RA (disease controls) were also tested. Anti-CEP1 IgG antibodies were measured with a commercially available ELISA kit (Euroimmun, Luebeck, Germany).Results:Anti-CEP1 titer was significantly higher in est-pSS, est-SLE and est-SSc compared to HD, significantly lower in est-pSS and est-SSc compared to est-RA and comparable in est-SLE versus est-RA. We divided patients in every CTD group based on whether their anti-CEP1 titer was below or above the 25th, 50th and 75th percentile. In est-SLE anti-CEP1 values over the 25th percentile were associated with articular involvement (odds ratio, OR (95% confidence interval, CI)=11.5; 1.9-70.6, p=0.008). In est-pSS, no relationship between anti-CEP1>25th percentile and articular involvement was found but rather an association with rheumatoid factor positivity (OR (95% CI)=4.8, 1.6-14.1, p=0.004) and salivary gland swelling (OR (95% CI)=6.2, 1.3-29.1, p=0.021). In est-SSc no difference could be detected across the 3 groups. Anti-CEP-1 titers in pSS and SLE at onset did not differ from each other, were comparable also to those of HD and significantly lower than those of est-pSS, est-SLE and est-RA patients (all pConclusion:Anti-CEP-1 antibodies can be detected in CTDs at different title during the disease course and may increase overtime, at least in pSS. Although anti-CEP1 antibodies are associated with specific clinical manifestation in est-CTDs, such as articular involvement in est-SLE, they seem to lack a predictive value for future manifestations when measured at disease onset.References:[1]Alunno A, Bistoni O, Pratesi F et al Rheumatology (Oxford) 2018.[2]Manca ML, Alunno A, D’Amato C et al. Joint Bone Spine 2018.Disclosure 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

Retrospective studies reported a high incidence of maternal complications in pregnant women with lupus. In this paper we prospectively assessed the rate of risk and the risk factors of maternal outcome in women with stable lupus nephritis who received pre-pregnancy counseling. This prospective multicenter study includes 71 pregnancies in 61 women with lupus nephritis who became pregnant between 2006 and 2013. Complete renal remission was present before pregnancy in 56 cases (78.9%) and mild active nephritis in 15 cases. All women underwent a screening visit before pregnancy and were closely monitored by a multidisciplinary team. Lupus anticoagulant, serum C3 and C4 complement fractions, anti-DNA antibodies, anti-C1q antibodies, anticardiolipin IgG and IgM antibodies, anti-beta2 IgG and IgM antibodies were tested at screening visit, at first, second, third trimester of pregnancy, and one year after delivery. Renal flares of lupus during or after pregnancy, pre-eclampsia, and HELLP syndrome were defined as adverse maternal outcomes. Fourteen flares (19.7%), six cases of pre-eclampsia (8.4%) and two cases of HELLP (2.8%) occurred during the study period. All flares responded to therapy and the manifestations of pre-eclampsia and HELLP were promptly reversible. Low C3, high anti-DNA antibodies and predicted all renal flares. High anti-C1q antibodies and low C4 predicted early flares. The body mass index (BMI) was associated with increased risk of late flares. History of previous renal flares and the presence of clinically active lupus nephritis at conception did not increase the risk of renal flares during pregnancy. History of renal flares before pregnancy, arterial hypertension, and longer disease predicted pre-eclampsia/HELLP. In pregnant women with lupus nephritis adverse maternal outcomes were relatively common but proved to be reversible when promptly diagnosed and treated. Immunological activity, arterial hypertension and BMI may predispose to maternal complications.

Patients affected with systemic lupus erythematosus (SLE) still display increased mortality and decreased quality of life in respect to general population. The major determinant of poor long term prognosis is organ damage, which is predictive of more damage and death. Damage is in turn triggered by uncontrolled disease activity and especially by the long-standing corticosteroid use which often accompanies SLE patients over their disease course, owing both to the need of reaching disease remission and to the habit of keeping patients on a small steroid dose for an indefinite period of time. Hence, the need for new drugs and therapeutic strategies aiming at minimizing damage accrual through a better control of disease activity and a steroid-sparing potential is paramount. So far, however, the therapeutic strategy in SLE requires a multitarget approach which is not devoid of widespread immunesuppression. In fact, several studies have been carried out in recent years targeting both the adaptive and the innate immune system, the majority of which did not achieve their primary endpoint, being often divergent from successful clinical experience and thereby committing physician to off-label use of targeted therapies in face of refractory SLE manifestations. The study designs and the chosen endpoints were often blamed for inadequacy, being at least in part responsible for study failures. In this review, we go over major clinical trials conducted in SLE by analyzing any critical aspects related to study design, predefined endpoints and biological activity of novel compounds that may have hampered study outcome, despite the great effort of providing less toxic drugs within a targeted, pathogenic-based approach.

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 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: SLEDAI is a widely used instrument to measure disease activity of systemic lupus erythematosus (SLE). However, it lacks sensitivity to discriminate improvement/worsening as it only scores items categorically and does not include several relevant lupus features, such as hemolytic anemia. Objectives: To derive and validate a SLE Disease Activity Score (SLE-DAS) with improved sensitivity to change, while maintaining the high specificity and simplicity of use of the SLEDAI. Methods: 324 patients fulfilling ACR’97 and/or SLICC’12 classification criteria for SLE and regularly followed at a tertiary care lupus clinic from January 2014 to December 2017 were included. At each outpatient visit, clinical and laboratory data were collected and disease activity (last 30 days) was scored with Physician Global Assessment (PGA) (0–3 scale) and SLEDAI-2K. To derive the SLE-DAS we analyzed data from the study visit with higher disease activity from each patient, applying multivariate linear regression analysis, with PGA as dependent variable/gold-standard. Independent variables tested in the models included items from SLEDAI-2K and continuous variables for swollen joint count, proteinuria, platelet and white blood cells counts. Some features absent from SLEDAI, such as hemolytic anemia, gastrointestinal and cardiopulmonary involvement were added to the model. To assess correlation validity we performed a Spearman’s correlation between the SLE-DAS, PGA and SLEDAI-2K at last follow-up visit. We tested performance of SLEDAI-2K (change ≥4) and SLE-DAS to discriminate a clinically meaningful worsening and improvement in SLE disease activity (change in PGA ≥0.3) using Receiver Operating Characteristic (ROC) curve analysis. We determined the best cut-offs values of SLE-DAS to detect changes in PGA ≥0.3 and calculated the sensitivity, specificity, positive and negative predictive values (PPV, NPV). Statistical significance was set at 0.05. Results: The final SLE-DAS model included 17 items. The SLE-DAS score at last follow-up visit presented high correlation with PGA (rho=0.975, p Conclusions: The SLE-DAS presents good construct validity and much higher discriminative power to detect changes in SLE disease activity as compared to SLEDAI-2K. External validation in another SLE cohort is underway. 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

Background The treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) is extremely challenging and only a few clinical trials have been performed to establish optimal management. Objectives To describe the therapeutic approach and the short-term outcome of a multi-centre cohort of patients with NPSLE, enrolled at the time of the first NP event. Methods This is a retrospective cohort study. All NP events were defined according to American College of Rheumatology (ACR) case definition and divided into 3 clusters: central/diffuse (C/D), central/focal (C/F) and peripheral (P). A validated attribution algorithm was used to determine the attribution of all NP events. Demographic variables, global SLE disease activity Index 2000 (SLEDAI-2K), cumulative organ damage (SLICC/ACR Damage Index (SDI)) and treatment adopted for NP manifestations were collected. The clinical outcome of all NP events was determined by a physician-completed seven-point Likert scale (1=patient demise, 2=much worse, 3=worse, 4=no change, 5=improved, 6=much improved, 7=resolved). The relationship between the variables of interest and the outcome was analysed by crude and adjusted logistic models and reported as Odds Ratio (OR) and 95% confidence intervals (95% CI). Results 461 SLE patients with at least one NP event were included. 91.8% of patients were female, mean (SD) age 35.4 (13.6) years. 19.7% (91) of events were observed at diagnosis of SLE, 13.4% (62) before and 66.8% (308) after the diagnosis. 111 events (24.1%) were C/F, 286 (62%) C/D and 64 (13.9%) P. 198 (42.95%) of all NP events were attributed to SLE. The overall probability of immunosuppressive therapy was 28.4% (95% CI 24.3–32.8), 38.7% (95% CI 29.6–48.5) in C/F, 21.3% (95%CI 16.7–26.5) in C/D and 42.2% (95%CI 16.7–26.5) in P manifestations. The probability of immunosuppressive therapy was 47.9% (95% CI 40.8–55.2) in attributed events. The one-year outcome was available in 355 patients. Physician assessment indicated resolution (76 patients) or improvement (150 patients) in 49% (226/461) of cases. The crude and adjusted OR of attributed NP events and immunosuppressants on a favourable outcome is illustrated in Figure 1. The multivariable logistic regression analysis was done adjusting for age at diagnosis of SLE [OR 0.96, 0.94–0.98] p=0.001, female gender [OR 0.97, 0.33–2.7] p=0.959, SDI [0.85, 0.68–1.08] p=0.202, SLEDAI-2K [1.06, 1.01–1.11] p=0.008 and type of event (F/C [REF], C/D [0.37, 0.16–0.83] p=0.016, P [0.54, 0.21–1.42] p=0.215). Conclusions In our study, the therapeutic immunosuppressive approach was mostly used in attributed, C/F and P manifestations. In patients treated with immunosuppressants, the favourable outcome was lower in C/D phenotype. 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

From the epidemiological and criminological points of view, murders committed by minors, including both victims and perpetrators, differ from those observed in adults. Analysis of trends and characteristics of murders at national level could provide useful information to assess the phenomenon and address political and social choices aiming at preventing violence involving children and adolescents. This study focuses on the trends of murders in Italy during the period 2007–2015 and compares the data with those for other age groups. Data on murders regarding trends, gender, age and ethnic group from the Italian Institute of Statistics were analysed by chi-square with odds ratio and linear regression. Results show that, after standardization, murders involving minors as victims and perpetrators were less frequent with respect to data observed in all age groups. Trend analysis showed that murders involving minors remained stable in the period considered, but the stability of the rate of murders of minors was in contrast with reduced rates in other age groups. Among minors, males aged 14–17 are at higher risk of being the perpetrators and victims of homicide. The rate of perpetrators and victims among foreign-born minors was higher than that among the native-born. Further studies are needed to determine risk factors associated with these results and to propose preventive strategies through appropriate policies and interventions.

ObjectiveTo evaluate the prevalence, duration and effect on damage accrual of the ‘Lupus Low Disease Activity State’ (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE).MethodsWe studied 293 Caucasian patients with SLE during a 7-year follow-up period. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SELENA-SLEDAI physician global assessment (PGA), and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We considered the following definition of LLDAS: SLEDAI-2K ≤4 without major organ activity, no new disease activity, PGA (0–3)≤1, prednisone ≤7.5 mg/day and well-tolerated immunosuppressant dosages. The effect of LLDAS on SDI was evaluated by multivariate regression analysis. We also evaluated remission defined as clinical SLEDAI-2K=0 and prednisone ≤5 mg/day in patients treated with/without stable immunosuppressants and/or antimalarials.ResultsLLDAS lasting 1, 2, 3, 4 or ≥5 consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%) and 109 (37.2%) patients, respectively. Patients who spent at least two consecutive years in LLDAS had significantly less damage accrual compared with patients never in LLDAS (p=0.001), and they were significantly less likely to have an increase in SDI (OR 0.160, 95% CI 0.060 to 0.426, pConclusionsLLDAS was associated with a decrease in damage progression in Caucasian patients with SLE. The majority of patients in LLDAS were in remission, which can largely contribute to the protective effect of LLDAS on damage accrual.

© 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, The term 'undifferentiated connective tissue disease' (UCTD) is generally used to describe clinical entities characterised by clinical and serological manifestations of systemic autoimmune diseases but not fulfilling the criteria for defined connective tissue diseases (CTDs). In this narrative review, we summarise the results of a systematic literature research, which was performed as part of the ERN ReCONNET project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. No specific CPG on UCTD were found, potential areas of intervention are absence of a consensus definition of UCTD, need for specific monitoring and therapeutic protocols, stratification of UCTD based on the risk of developing a defined CTD and preventive measure for the future development of a more severe condition. Patients feel uncertainty regarding the name of the disease and feel the need of a better education and understanding of these conditions and its possible changes over time., This publication was funded by the European Union’s Health Programme (2014-2020).

Objective To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice. Patients and methods Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software. Results We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found. Conclusion Belimumab is effective and safe when used in clinical practice setting.

To date, belimumab is the only biological drug approved for the treatment of patients with active refractory SLE. We compared and critically analyzed the results of 11 observational clinical-practice-based studies, conducted in SLE referral centers. Despite the differences in endpoints and follow-up duration, all studies remarked that belimumab provides additional benefits when used as an add-on to existing treatment, allowing a higher rate of patients to reach remission and to taper or discontinue corticosteroids. In the OBSErve studies, 2–9.6% of patients discontinued corticosteroids and 72–88.4% achieved a ≥ 20% improvement by physician’s judgment at 6 months. In Hui-Yuen’s study, 51% of patients attained response by simplified SRI at month 6. In Sthoeger’s study, 72.3% of patients discontinued corticosteroids and 69.4% achieved clinical remission by PGA after a median follow-up of 2.3 years. In the multicentric Italian study, 77 and 68.7% of patients reached SRI-4 response at months 6 and 12, respectively. In all the studies, disease activity indices decreased over time. Retention rates at 6, 9, and 12 months were 82–94.1, 61.2–83.3, and 56.7–79.2%, respectively. The main limitations of these studies include the lack of a control group, the short period of observation (6–24 months) and the lack of precise restrictions regarding concomitant medication management. This notwithstanding, these experiences provide a more realistic picture of real-life effectiveness of the drug compared with the randomized controlled clinical trials, where stringent inclusion/exclusion criteria and changes in background therapy could limit the inference of data to the routine clinical care.

ObjectivesTo derive and validate a new disease activity measure for systemic lupus erythematosus (SLE), the SLE Disease Activity Score (SLE-DAS), with improved sensitivity to change as compared with SLE Disease Activity Index (SLEDAI), while maintaining high specificity and easiness of use.MethodsWe studied 520 patients with SLE from two tertiary care centres (derivation and validation cohorts). At each visit, disease activity was scored using the Physician Global Assessment (PGA) and SLEDAI 2000 (SLEDAI-2K). To construct the SLE-DAS, we applied multivariate linear regression analysis in the derivation cohort, with PGA as dependent variable. The formula was validated in a different cohort through the study of: (1) correlations between SLE-DAS, PGA and SLEDAI-2K; (2) performance of SLEDAI-2K and SLE-DAS in identifying a clinically meaningful change in disease activity (ΔPGA≥0.3); and (3) accuracy of SLEDAI-2K and SLE-DAS time-adjusted means in predicting damage accrual.ResultsThe final SLE-DAS instrument included 17 items. SLE-DAS was highly correlated with PGA (r=0.875, pConclusionSLE-DAS has a good construct validity and has better performance than SLEDAI-2K in identifying clinically significant changes in disease activity and in predicting damage accrual.

The objective was to evaluate renal involvement in several rheumatic diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, systemic vasculitides). The method chosen was to define histopathological profiles reported in renal biopsies performed on patients with renal involvement due to different rheumatic diseases. Renal involvement observed in patients with rheumatic disease can be the direct result of the disease per se and/or a complication of drugs used in the disease treatment. The clinical-pathological correlations derived from the study of renal tissues can be useful for differential diagnosis, prognosis assessment and therapeutic decisions. Renal biopsy should be considered as an important tool for the management of nephropathies in patients with systemic rheumatic diseases.

National statistics on female homicide could be a useful tool to evaluate the phenomenon and plan adequate strategies to prevent and reduce this crime. The aim of the study is to contribute to the analysis of intentional female homicides in Italy by comparing Italian trends to German and United States trends from 2008 to 2014. This is a population study based on data deriving primarily from national and European statistical institutes, from the U.S. Federal Bureau of Investigation's Uniform Crime Reporting and from the National Center for Health Statistics. Data were analyzed in relation to trends and age by Chi-square test, Student's t-test and linear regression. Results show that female homicides, unlike male homicides, remained stable in the three countries. Regression analysis showed a higher risk for female homicide in all age groups in the U.S. Middle-aged women result at higher risk, and the majority of murdered women are killed by people they know. These results confirm previous findings and suggest the need to focus also in Italy on preventive strategies to reduce those precipitating factors linked to violence and present in the course of a relationship or within the family.

Objectives To evaluate survival of prednisone (PDN) – free remission in systemic lupus erythematosus (SLE) patients and to investigate the potential predictors of disease flares. Methods Inclusion criteria were: (1) Diagnosis of SLE according to American College of Rheumatology (ACR) Classification Criteria of SLE; (2) Caucasian ethnicity; (3) Clinical remission (clinical SLEDAI-2K=0) at the time of PDN-withdrawal; (4) Stop of PDN treatment between 2010 and 2016; (5) At least two visits per year between January 2010 and April 2016. Disease activity was assessed according to SLE Disease Activity Index-2000 (SLEDAI-2K). Damage was measured by the SLICC/American College of Rheumatology Damage Index (SDI). Flares were defined according to Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI criteria. We evaluated whether gender, age, age at PDN-stop, disease duration, duration of corticosteroid therapy, duration of remission before PDN withdrawal, time to flare, SLICC/American College of Rheumatology Damage Index (SDI) – score >3, positive anti-dsDNA antibodies (abs) and-or low C3/C4, type of SLE-involvement and concomitant immunosuppressive treatment could be predictors of flare. Multivariate logistic regression analysis was run to investigate the predictors of flare. Covariates included in the analysis were all variables reaching p Results Among 400 patients evaluated, 104 (26%) fulfilled inclusion criteria. Baseline characteristics are reported in table 1. Twenty-two (21.2%) patients flared. Mean time to flare was 19.91±13.14 months. Types of flare were 7 renal, 7 articular, 4 cutaneous, 2 haematological, 1 serositic and 1 neurological. Variables included in the multivariate logistic regression analysis were: positive anti-dsDNA abs and-or low C3/C4, skin, articular and haematological involvement. Skin involvement resulted predictive of flare (OR 3.07, 95% CI 1.11–8.53, P 0.031) as reported in table 2. Conclusions In SLE patients who stopped corticosteroid therapy, previous skin involvement resulted to be a predictor of disease flare. Disclosure of Interest None declared

Background Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are multi-systemic diseases associated with anti-neutrophil cytoplasmic antibodies (ANCA). Patients develop severe and irreversible damage, even in early stages of the disease, but data about prognostic factors are limited. Objectives To assess items and predictors of severe damage in a monocentric cohort of ANCA-associated vasculitis (AAV) patients, classified as GPA or MPA. Methods Clinical and serological data of patients, followed-up in a daily practice setting, were retrospectively revised. Severe damage, defined as a Vasculitis Damage Index (VDI) 3 5, was assessed after 12 months and at last examination (LE). The five most important items, predictors of severe damage and their increase rate were analysed at the beginning and at the last examination. Results 69 patients were included, 53 (76.8%) classified as GPA and 16 (23.2%) as MPA. According to EUVAS classification 7 (10.1%) were affected by limited disease, 14 (20.3%) by early systemic disease, 35 (50.7%) by generalized disease and 13 (18.9%) by severe disease. Patients were middle aged at diagnosis (54.6±15 years) with a diagnostic latency of 9.6±16.4 months, mostly caucasian (98.6%) and equally represented in sex (female 53.6%). Mean follow-up was 54.5±41.9 months. The number of flare/year at LE was significantly higher in anti-PR3 patients if compared to anti-MPO (1.0±1.1 vs 0.3±0.5, p=0.028). The VDI items most frequently observed are listed in Figure 1. We measured their frequencies and increase rate from diagnosis to the LE: arterial hypertension increased from 3 (4.7%) to 41 (65.1%) (+60.3% (IC 95% 48–71%), p 0.5 g 24 h from 1 (1.6%) to 13 (20.6%) (+19% (IC 11–31); p=0.0006). Severe damage, defined as VDI≥5, increased over time, being present in none patient at diagnosis and in 14 (25.9%) at last examination. At univariate analysis, number of flares/year (p=0.012), BVASv3 at diagnosis (p=0.03), steroid pulses therapy (p=0.04) and steroid cumulative dose (p=0.03) were identified as predictive factors of severe damage in the first year. Conversely, creatinine at LE (p=0.04), numbers of hospitalizations (p=0.009) and steroid cumulative dose at LE (p=0.47) were found to be predictors of long-term severe damage. Interestingly, ANCA pattern did not influence damage severity and only slightly differences in VDI items was noted between anti-PR3 and anti-MPO positive patients. Conclusions Our results highlights that knowing severe damage predictors is key in short and long term treat to target patient9s management. Disclosure of Interest None declared

Background and aims To assess the prevalence and validate the effect on damage accrual of the recently defined “Lupus Low Disease Activity State”(LLDAS) in a monocentric cohort of patients with Systemic Lupus Erythematosus (SLE). Methods We studied 293 Caucasian SLE patients during 7 year follow-up. Disease activity was assessed by SLEDAI-2K and SELENA-SLEDAI physician global assessment (PGA), and damage by SLICC/ACR Damage Index (SDI). Franklyn et al 1 definition of LLDAS was applied: (1) SLEDAI-2K≤4, with no activity in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus activity compared with the previous assessment; (3) a PGA (scale 0–3)≤1; (4) current prednisolone-equivalent dose ≤7.5 mg/day; (5) stable maintenance dose of immunosuppressants. The effect of different durations of LLDAS (1, 2, 3, 4,≥5 consecutive years) on SDI was evaluated by multivariate logistic regression analysis. Results The prevalence of LLDAS and damage in the cohort are reported in Table 1. Patients who spent at least 2 consecutive years in LLDAS had significantly reduced damage accrual compared with patients never in LLDAS (p=0.001). Interestingly, among the 254 patients achieving LLDAS for at least 1 year, 231 (90.9%) had clinical-SLEDAI-2K=0. At multivariate analysis, a LLDAS lasting at least two years was protective against damage (Table 2). Conversely, major independent predictors of damage were cumulative prednisone dose ≥180 mg/month and antiphospholipid antibody syndrome (Table 2). Conclusions Two consecutive years was the shortest LLDAS duration associated with a decrease in damage progression in Caucasian SLE patients. Reference Franklyn K, et al . Ann Rheum Dis 2016; 75 :1615–1621.

Background and aims To investigate effectiveness, damage accrual and predictors of response to belimumab in active SLE patients in clinical practice setting. Methods 188 active SLE patients with anti-dsDNA antibodies and low C3 and/or C4, from 11 Italian centres, were treated with belimumab as add-on-therapy. Gender, age, disease duration, polyarthritis, skin rashes, glomerulonephritis, haematological involvement, SLEDAI-2K≥10, prednisone ≥7,5 mg/day and concomitant immunosuppressants were used to determine baseline predictors of 12- and 24 month response according to SRI-4. Data were analysed by SPSS (version 22.0). Results Prominent clinical manifestations are summarised in Table 1. Clinical and serological variables at baseline, 12 and 24 months are reported in Table 2. SRI-4 was achieved by 71.3% and 68.7% of patients at 12 and 24 months, respectively. 92% of 12 month responders maintained SRI-4 response at 24 months; conversely, 87.5% of non-responders at 12 months were non-responders even at 24 months. Drug discontinuation for any cause was observed in 36.2% of patients; median treatment duration was 12 months. Damage accrual variation was significant between 5 years before drug initiation and baseline (p Conclusions Belimumab seems to be effective and to reduce damage accrual in SLE patients in clinical practice setting. Patients with arthritis and high disease activity were the best responders to belimumab.

Background and aims To explore predictors of renal remission, insufficiency and damage in lupus nephritis (LN). Methods We retrospectively analysed our lupus cohort and studied LN patients with at least one renal biopsy since 1990 until 2016. Follow-up ended at last patient visit. Complete renal remission (CRR) was defined as proteinuria 0.5 g/day and/or requirement for treatment modifications. Damage was measured by SLICC damage index (SDI). Results 81 patients were studied (Table) who underwent 110 biopies. Forty patients (49.3%) went into CRR by the end of follow-up. Thirty-six (44.5%) had 2 renal flares while 21≥3 (26%). Six patients developed renal failure preceded by ≥3 flares in 5. One case of ESRD was reported. By the end of follow-up 30 patients (37%) had SDI≥2. At univariate analysis, increased proteinuria at 12 and 24 months from first biopsy and higher flare number were inversely associated with CRR, while long-lasting hypertension, abnormal SCr, decreased GFR and C4 at time of first biopsy were associated with renal failure. At multivariate analysis 24h-proteinuria at 24 months independently predicted lack of CRR (OR 3.7), while a higher number of renal flares (OR 5.27), higher SCr at 6 months from renal biopsy (OR 5.01) and a longer disease duration (OR 6.34) were independently associated with damage accrual. Conclusions Increased proteinuria and abnormal baseline renal function make CRR unlikely. Suboptimal control of LN activity and longer disease duration are associated with severe damage accrual.

To investigate effectiveness and safety of belimumab in patients with active systemic lupus erythematosus (SLE) in a clinical practice setting.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).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 0.001), particularly in those with CLP (P 0.001), and CLASI decreased in patients with skin manifestation (P = 0.003), either ACLE (P = 0.051) or SCLE (P = 0.047). Flare rate was lower 1 and 2 years after belimumab initiation than in the periods before (P = 0.001). Belimumab was well-tolerated and no damage accrual was observed after initiation.Belimumab was effective and safe in a clinical practice setting; it decreased the number of flares and hindered damage progression in patients with active SLE.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, characterized by the production of autoantibodies by autoreactive B cells, which are capable of inducing inflammatory changes in various organs and systems by several mechanisms. In patients with SLE, all the cardiac structures can be involved. Pericarditis is the most common cardiac abnormality, but lesions of the valves, myocardium, and coronary vessels may also occur. Nowadays, cardiac manifestations can be frequently recognized by echocardiography and other noninvasive tests, such as cardiac computed tomography or cardiac magnetic resonance imaging. Echocardiography is a nonexpensive, sensitive, and specific technique in detecting cardiac abnormalities, particularly mild pericarditis, valvular lesions, and myocardial dysfunction. Premature atherosclerosis is the most frequent cause of coronary artery disease in SLE patients. Efforts should be made to control traditional risk factors as well as all other factors, which could contribute to atherosclerotic plaque development.

The aim of our study was to analyze olfactory function in patients with idiopathic inflammatory myopathies (IIM). We performed a case–control study on 60 IIM patients (48 females and 12 males) and 60 healthy controls (HC) recruited by the best friend method, matched for age, sex and lifestyle. Olfactory function was analyzed by “Sniffin’ sticks test” and expressed through a score (TDI), indicating normosmia (TDI > 30), hyposmia (TDI 15–30) and anosmia (TDI

Idiopathic inflammatory myopathies (IIM) are a rare disease; so far standardized therapy has not been adequately defined by national or international guidelines or recommendations. Corticosteroids are the mainstay of treatment, but these drugs are burdened by several side effects. Thus, additional treatment based on immunosuppressive agents, especially azathioprine, methotrexate, mycophenolate mofetil and cyclosporine, is often needed. This combinate approach both improves the disease response and allows reduction of the dosage of corticosteroids, decreasing the risk of steroid-related long-term complications. Biological agents, particularly B cell depleting agent, are emergent therapeutic tools for refractory cases. Notably, drugs currently used for the therapy of IIM or other rheumatologic and non-rheumatologic conditions can induce myopathy. Drug-induced myopathies represent a considerable part of the complex topic of muscular disorders and should be always considered in the usual diagnostic work-up of a subject with muscle disease. Several mechanisms have been advocated to explain muscular damage induced by a number of drugs and, although a recovery after drug removal is usually observed, severe or persistent myopathy may be observed following the administration of some drugs, particularly in subjects with genetic predisposition. In this review the traditional and novel therapeutic approaches for patients with IIM, particularly biologics, will be discussed and an overview on drug-induced myopathies will also be provided.

Patients with systemic lupus erythematosus (SLE) have a higher prevalence of clinical and subclinical atherosclerosis compared with age- and sex-matched controls. Atherosclerosis progression is also accelerated in SLE, and coronary heart disease (CHD) is a major cause of morbidity and mortality. Traditional cardiovascular (CV) risk factors, including hypertension, diabetes mellitus or dyslipidemia, are more prevalent in SLE patients than in the general population, but they cannot fully account for accelerated atherosclerosis in SLE. In fact, a number of nontraditional risk factors have been identified, including disease activity, damage and various treatments. Preventive strategies for CHD are mandatory in SLE patients and should include giving up smoking; performing regular physical activity; managing metabolic abnormalities such as dyslipidemia, insulin resistance, and diabetes; treating persistent disease activity; and minimizing chronic exposure to corticosteroids. Low-dose aspirin, angiotensin-converting enzyme (ACE) inhibitors, vitamin D supplementation, antimalarials and, when indicated, some immunosuppressants such as mycophenolate mofetil should also be considered.

We read with great interest the article from Wilhelm et al 1 published on Annals of the Rheumatic Diseases. We agree with the authors that remission is an emerging concept in systemic lupus erythematosus (SLE) and that it is very important to find out a definition of remission heralding the best outcome for clinical practice and clinical trials. Although this study, carried out in a very large monocentric cohort of lupus patients, is an important contribution to this topic, its result is a little bit disappointing: indeed, only a minority of lupus patients could maintain a durable remission, …

AimTo identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE).MethodsWe studied 293 Caucasian patients with SLE during 7-year follow-up. Disease activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1–5 mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis.ResultsAmong patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (pIn multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2 years 0.228 (0.061 to 0.850); 3 years 0.116 (0.031 to 0.436); 4 years 0.118 (0.027 to 0.519) and ≥5 years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180 mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)).ConclusionsTwo consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.

The aim of this multicenter study was to assess the present risk of fetal complications and the inherent risk factors in pregnant women with lupus nephritis. Seventy-one pregnancies in 61women (59 Caucasians and 2 Asians) with lupus nephritis were prospectively followed between October 2006 and December 2013. All patients received a counselling visit within 3 months before the beginning of pregnancy and were followed by a multidisciplinary team. At baseline mild active nephritis was present in 15 cases (21.1%). Six pregnancies (8.4%) resulted in fetal loss. Arterial hypertension at baseline (P = 0.003), positivity for lupus anticoagulant (P = 0.001), anticardiolipin IgG antibodies (P = 0.007), antibeta2 IgG (P = 0.018) and the triple positivity for antiphospholipid antibodies (P = 0.004) predicted fetal loss. Twenty pregnancies (28.2%) ended pre-term and 12 newborns (16.4%) were small for gestational age. Among the characteristics at baseline, high SLE disease activity index (SLEDAI) score (P = 0.027), proteinuria (P = 0.045), history of renal flares (P = 0.004), arterial hypertension (P = 0.009) and active lupus nephritis (P = 0.000) increased the probability of preterm delivery. Odds for preterm delivery increased by 60% for each quarterly unit increase in SLEDAI and by 15% for each quarterly increase in proteinuria by 1 g per day. The probability of having a small for gestational age baby was reduced by 85% in women who received hydroxychloroquine therapy (P = 0.023). In this study, the rate of fetal loss was low and mainly associated with the presence of antiphospholipid antibodies. Preterm delivery remains a frequent complication of pregnancies in lupus. SLE and lupus nephritis activity are the main risk factors for premature birth. Arterial hypertension predicted both fetal loss and preterm delivery. Based on our results the key for a successful pregnancy in lupus nephritis is a multidisciplinary approach with close medical, obstetric and neonatal monitoring. This entails: a) a preconception evaluation to establish and inform women about pregnancy risks; b) planning pregnancy during inactive lupus nephritis, maintained inactive with the lowest possible dosage of allowed drugs; c) adequate treatment of known risk factors (arterial hypertension, antiphospholipid and antibodies); d) close monitoring during and after pregnancy to rapidly identify and treat SLE flares and obstetric complications.

Around 1980 antinuclear antibody testing became widely used in routine laboratory practice leading to a tapering in the lag time between SLE onset and diagnosis. Since then nothing relevant has been introduced which could help us in making the diagnosis of SLE earlier than now. Notably, there is increasing evidence that early diagnosis and treatment could increase SLE remission rate and improve patient prognosis. Although it has been shown that autoantibodies appear before clinical manifestations in SLE patients, currently we cannot predict which autoantibody positive subjects will eventually develop the disease. Thus, great effort should be made in order to identify new biomarkers able to improve our diagnostic potential. B lymphocyte stimulator (BLyS), anti-ribosomal P protein and anti-C1q antibodies are among the most promising. In recent years, some therapeutic options have emerged as appropriate interventions for early SLE treatment, including antimalarials, vitamin D, statins and vaccination with self-derived peptides. All these immune modulators seem to be particularly useful when introduced in an early stage of the disease.

Impairment of the clearance of apoptotic material seems to contribute to autoantigen exposure, which can initiate or maintain an autoimmune response in predisposed individuals. Complement component C1q, Creactive protein (CRP), serum amyloid P (SAP), mannose-binding lectin (MBL), apolipoprotein A-1 (Apo A-1) and long pentraxin 3 (PTX3) are molecules involved in the removal of apoptotic bodies and pathogens, and in other antiinflammatory pathways. For this reason they have been called “protective” molecules. C1q has a key role in the activation of the complement cascade and acts as a bridging molecule between apoptotic bodies and macrophages favouring phagocytosis. In addition to other functions, CRP, SAP and MBL bind to the surface of numerous pathogens as well as cellular debris and activate the complement cascade, thus stimulating their clearance by immune cells. The role of PTX3 is more controversial. In fact, PTX also promotes the clearance of microorganisms, but the activation of the complement cascade through C1q and removal of apoptotic material can be either stimulated or inhibited by this molecule. Antibodies against protective molecules have been recently reported in systemic lupus erythematosus and other autoimmune rheumatic diseases. Some of them seem to be pathogenetic and others protective. Thus, protective molecules and their cognate antibodies may constitute a regulatory network involved in autoimmunity. Dysregulation of this system might contribute to the development of autoimmune diseases in predisposed individuals.

We appreciated the comments by Ugarte-Gil and co-authors1 on our report dealing with lupus low disease activity state (LLDAS) in Caucasian patients.2 We agree that Caucasian patients with systemic lupus erythematosus (SLE) have a better prognosis compared with non-Caucasian ones, but, in our opinion, race does not fully elucidate the different results in terms of prevalence of low disease activity and remission obtained in the studies by Zen et al 2 and Ugarte-Gil et al .3 The different design of the studies is more relevant than race in explaining the divergent results. Indeed, the Grupo Latino Americano De Estudio del Lupus (GLADEL) study3 analysed an inception cohort of patients shortly after the disease onset (median disease duration 0.3 years), and the authors assessed remission and low disease activity status (LDAS) during the first years of follow-up. …

A growing body of experimental and clinical evidence supports the pivotal role of infections in the induction or exacerbation of systemic lupus erythematosus (SLE). Infections can be responsible for aberrant immune response leading to a loss of tolerance towards native proteins. Molecular mimicry, especially between Sm or Ro autoantigens and EBV Nuclear Antigen-1 response, as well as the over-expression of type 1 INF genes are among the major contributors to SLE development. On the other hand infections are very common in SLE patients, where they are responsible for 30-50% of morbidity and mortality. Several factors, either genetic, including complement deficiencies or mannose-binding lectin deficiency or acquired such as severe disease manifestations or immunosuppressant use, predispose SLE patients to infections. All types of infections, including bacterial, viral and opportunistic infections, have been reported and the most frequently involved sites of infections are the same as those observed in the general population, including respiratory, skin, and urinary tract infections. Some preventive measures could be adopted in order to reduce the rate of infections in SLE patients: i.e. screening for Mycobacterium tuberculosis and for some chronic viral infections before immunosuppressive treatment; adequate prophylaxes or drug adjustments when indicated, and pneumococcal and influenza vaccinations in patients with stable disease.

Pentraxin 3 (PTX3) is an acute-phase protein involved in C1q clearance. The presence of anti-C1q and the absence of anti-PTX3 antibodies were associated with lupus glomerulonephritis (LGLN). Our aim was to assess soluble and kidney-expressed PTX3 and their relationships with anti-C1q and anti-PTX3 antibodies in LGLN. Serum PTX3, anti-C1q, anti-dsDNA, and anti-PTX3 antibodies were tested in 130 systemic lupus erythematosus (SLE) patients, 130 healthy and 127 disease controls. Twenty-nine renal biopsies from SLE patients were analyzed and PTX3 immunostaining was quantified by morphometric analysis. Parametric and nonparametric statistics were performed. PTX3 serum levels were lower in SLE versus controls, but they were correlated with proteinuria in LGLN patients (p = 0.001). LGLN patients had higher anti-C1q and lower anti-PTX3 antibody levels than those without (p

AimTo assess the prevalence of prolonged remission in Caucasian patients affected with systemic lupus erythematosus (SLE) and its relationship with damage accrual.MethodsCaucasian patients diagnosed with SLE between 1990 and 2009 and quarterly seen from 2009 to 2013 were included in the study. We defined remission as prolonged when lasting ≥5 consecutive years. Three levels of remission were defined using the SLE Disease Activity Index-2000 (SLEDAI-2K): complete remission: no disease activity in corticosteroid-free and immunosuppressant-free patients; clinical remission off corticosteroids: serologically active clinical quiescent (SACQ) disease in corticosteroid-free patients and clinical remission on corticosteroids: SACQ disease in patients taking prednisone 1–5 mg/day. Damage was measured by the SLICC/American College of Rheumatology Damage Index (SDI).Results224 patients fulfilled inclusion criteria: 196 (87.5%) were women, mean±SD disease duration 11.2±6.8 years. During the 5-year follow-up, 16 patients (7.1%) achieved prolonged complete remission, 33 (14.7%) prolonged clinical remission off corticosteroids and 35 (15.6%) prolonged clinical remission on corticosteroids. At the multivariate analysis, vasculitis (OR 4.95), glomerulonephritis (OR 2.38) and haematological manifestations (OR 2.19) over the patients’ disease course were associated with an unremitted disease. SDI increased more frequently in unremitted (72/140, 51.4%) than in remitted patients (22/84, 26.2%; p=0.001); SDI median increase was higher in unremitted than in remitted patients: 1 (0–3) vs 0 (0–2), respectively (pConclusionsThirty-seven percent of our Caucasian patients achieved a prolonged remission, which was associated with a better outcome in terms of damage accrual.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of conditions characterized by muscle inflammation and a variety of extra-muscular features, including fever, weight loss, and immunologic abnormalities. The major categories of IIM are dermatomyositis, polymyositis, necrotizing immune-mediated myositis, and inclusion body myositis. The pathogenesis of IIM has not been completely elucidated, but there is evidence that environmental factors, including infectious agents, trigger an abnormal autoimmune response in genetically susceptible individuals, leading to organ damage. In this chapter, we discuss the role of infectious agents as initiating factors in disease induction. Experimental findings in animal models of infection-induced myositis and epidemiological studies of humans that support this hypothesis are summarized here. Finally, considering that infections and cancer are the most common causes of death and morbidity among patients with IIM, the increased risk of developing infections in these patients is also discussed.

Patients affected with systemic lupus erythematosus (SLE) display poor-long term prognosis and increased mortality in respect of general population. This may be due to continuous organ damage accrual which is fostered both by persistent disease activity (mainly in the short term) and prolonged corticosteroid exposure (mainly in the long term). The effort of defining novel therapeutic goals to which patients should be treated in order to have their prognosis improved is named treat-to-target. Remission in SLE was shown to be associated with better outcome and prolonged survival; in clinical practice, patients may experience either complete or clinical remission, which are defined as complete clinical/serological healing or no clinical signs of lupus with active serology, respectively. The main treat-to-target in SLE is complete remission, however since longitudinal observations suggest that clinical remission or low disease activity even with minimal corticosteroid intake do improve patients prognosis and survival as well, they may be assumed as acceptable alternative targets. Suitable therapeutic strategies have to be defined in order for these goals to be achieved including early diagnosis, effective treatment and proper corticosteroid tapering which in turn require development of more reliable serum biomarkers for early disease detection and less toxic targeted therapies with a steroid-sparing potential.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by an inflammatory infiltrate primarily affecting the skeletal muscle and skin. Most common and peculiar cutaneous lesions include Gottron's papules, Gottron's sign and heliotrope rash. Different DM subsets have been identified until now encompassing classic DM, amyopathic DM, hypomyopathic DM, post-myopathic DM, and DM sine dermatitis. Patients with DM have a higher incidence rate of malignancy than the normal population. In these patients cancer occurs in about 30% of cases with higher occurrence in men and in elderly people. Bohan and Peter's diagnostic criteria, proposed in 1975, have been widely accepted and used until now. In the last ten years muscle immunopathology, myositis specific autoantibodies testing, and the use of new techniques of muscle imaging such as contrast-enhanced ultrasound or Magnetic Resonance Imaging have been introduced in the diagnostic work-up of patients with DM leading to the development of new diagnostic criteria.