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Objectives To describe phenotypes and outcomes of extra-renal flares in SLE, to identify clusters of extra-renal flares based on baseline features, and to develop a machine learning (ML) tool capable of predicting ‘difficult to treat’ (D2T) flares. Methods Extra-renal flares that occurred in our cohort over the last five years with at least one year of follow-up were included. Baseline clinical variables were described and flares assigned to clusters. Attainment of remission and low disease activity state (LLDAS) at 12 months were compared. Flares were then considered ‘D2T’ in case of non-attainment of LLDAS at 6 and 12 months. Baseline features were used to train a ML model able to predict future D2T-flares, at admission. Traditional approaches were then compared with informatic techniques. Results Among 420 SLE patients of the cohort, 114 flares occurred between 2015 and 2021; 79 extra-renal flares, predominantly mucocutaneous (24.1%) and musculoskeletal (45.6%), were considered. After 12 months, 79.4% and 49.4% were in LLDAS and in remission, respectively, while 17 flares were classified as D2T (21.5%); D2T flares received a higher cumulative and daily dose of glucocorticoids. Among the clusters, cluster ‘D’ (mild-moderate flares with mucocutaneous manifestations in patients with history of skin involvement) was associated with the lowest rate of remission. Among clinical data, not being on LLDAS at 3 months was the unique independent predictor of D2T flares. Conclusions Our clusterization well separates extra-renal flares according to their baseline features and may propose a new identification standard. D2T flares, especially refractory skin manifestations, are frequent in SLE and represent an unmet need in the management of the disease as they are associated with higher glucocorticoid (GC) dosage and risk of damage accrual. Our ML model could help in the early identification of D2T flares, flagging them to elevate the attention threshold at admission.

Systemic lupus erythematosus (SLE) is a chronic multisystem auto-immune disease with extremely varied clinical manifestations and a complex pathogenesis. New insights in SLE about pathogenetic pathways, biomarkers, and data on clinical manifestations are progressively emerging, and new drugs and new therapeutic strategies have been proposed to improve the control of disease activity. Thus, this review is aimed to summarise the most relevant data about SLE emerged during 2021, following the previous annual review of this series.

This case report describes 2 women with severe and refractory discoid lupus erythematosus that was treated with anifrolumab.

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

Treat-to-target is a therapeutic approach based on adjustments to treatment at set intervals in order to achieve well-defined, clinically relevant targets. This approach has been successfully applied to many chronic conditions, and in rheumatology promising results have emerged for rheumatoid arthritis. For systemic lupus erythematosus (SLE), defining the most meaningful treatment targets has been challenging, due to disease complexity and heterogeneity. Control of disease activity, the reduction of damage accrual and the patient’s quality of life should be considered as the main targets in SLE, and several new drugs are emerging to achieve these targets. This review is focused on describing the target to achieve in SLE and the methods to do so, and it is also aimed at discussing if treat-to-target could be a promising approach also for this complex disease.

BackgroundSLE is an autoimmune disease that predominantly affects women. As most epidemiological and interventional studies are on populations with a clear female prevalence, the influence of gender in disease course, drug response and damage accrual is yet to be fully explored and comprehended.ObjectivesTo describe gender differences in disease course, comorbidities, use of medications and long-term outcomes of a large cohort of patients with SLE.MethodsRetrospective gender-based analysis of prospectively collected data from a monocentric cohort of Caucasian patients with SLE with at least 1 year of follow-up.Results417 patients were included, 51 men and 366 women. Men displayed a significantly higher median age at disease onset and diagnosis and a higher prevalence of late-onset SLE, serositis at disease onset, antiphospholipid syndrome (APS) and use of mycophenolate within the first year of disease. Women had a higher prevalence of haematological abnormalities, a higher cumulative exposure to azathioprine and higher cumulative dose of glucocorticoids at 5 years. Male patients had a shorter time to first damage item and a higher prevalence of damage at 1 and 5 years, but this association was no longer significant when late-onset patients were excluded. No differences were found in prevalence of childhood onset, delay between onset and diagnosis, time to renal involvement and histology, cumulative autoantibody positivity, number of flares and hospitalisations, median SLE Damage Index score, type of damage, age and time to first cardiovascular event, chronic kidney disease and death.ConclusionsIn our cohort, clinical manifestations and disease course were similar in male and female patients; however, male patients displayed higher prevalence of APS and early damage accrual probably due to the later disease onset. These data highlight the importance of an intensive follow-up, prevention and treatment of complications in this category of patients, especially in the first years of disease.

Objective to describe the disease path and the very long-term outcome in a monocentric cohort of patients with Systemic Lupus Erythematosus (SLE). Methods SLE patients with a disease duration of at least 15 years from diagnosis were enrolled. The number of hospitalizations, the disease flares occurred over the disease course and the organ damage accumulation were evaluated at 1, 2, 3, 4, 5, 10 years from diagnosis and at last observation in 2019 as well. Disease state, ongoing therapies and quality of life measures were also assessed at last visit. Results 126 Caucasian SLE patients were included in the analysis (95% female, median age 47.5 IQR 41–53, median disease duration 21 IQR19-26). At last visit, the majority of the patients (78.6%) was on LLDAS (remission included), 53.4% were on GC treatment and 35.7% on immunosuppressant. Furthermore, 53.2% had at least one organ damage. The majority of patients (66.7%) presented a relapsing-remitting course, for a total of 158 flares during the disease course (incidence rate: 0.79/patient-year); moreover, 84.9% of the cohort experienced at least one hospital admission, amounting to a total of 328 hospitalizations (incidence rate: 0.85/patient-year). The main reason for admission was disease activity, while the percentage of hospitalizations due to other causes has been growing over the 10 years of follow-up. Conclusion after a very long period of disease, most of the patients with SLE are in remission and are not taking GC therapy; however, the risk of incurring in disease flare remains a real problem.

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.

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

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

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers’ pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

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 The attainment of remission and low disease activity (LLDAS) in SLE is associated with better outcomes. This study was aimed to test whether disease remission and LLDAS at the beginning of pregnancy are associated with better pregnancy outcomes. Methods A total of 85 pregnancies in 61 SLE patients prospectively followed at a single center were considered; 10 pregnancies ended in spontaneous abortion during the first trimester and were excluded from the analysis. Definitions of remission (according to DORIS criteria) and LLDAS were applied at the first pregnancy visit (7–8 weeks of gestational age). Disease flare was defined according to the SELENA-SLEDAI flare index. Obstetric complications included pretermprelabour rupture of membranes, preeclampsia, preterm delivery, SGA infant, IUGR, intrauterine fetal death (IUFD) and gestational diabetes. Results Characteristics of the cohort are detailed in table 1. In twenty-one cases (28%) we observed flare during pregnancy or puerperium. Two severe flares and 19 mild-moderate flares were recorded. Obstetric complications were observed in 31 cases (41%). The risk of disease flare during pregnancy was significantly lower in patients in LLDAS at the beginning of pregnancy with respect to active patients (OR 12.47, p Conclusions These data confirm that disease remission is one important predictor of pregnancy outcomes in SLE. While serology seems not to have a substantial role, a residual disease activity at conception might impact on pregnancy outcomes. Available definitions of remission and LLDAS could be valid treatment targets in the family planning perspective.

Objectives The Brief Index of Lupus Damage (BILD) is an instrument of self-evaluation of organ damage for systemic lupus erythematosus (SLE) patients. The objectives of this study were the translation, cultural adaptation and validation of the Italian version of the BILD (BILDit). Methods The process of translation and cultural adaptation followed published guidelines. The BILDit was pretested in a pilot study with 30 SLE patients in order to evaluate acceptability, reliability, comprehension and feasibility, and then validated in consecutive SLE patients attending our clinic. Results A total of 167 SLE patients were enrolled. In the pilot study, the BILDit demonstrated good acceptability, feasibility and comprehensibility and a very high degree of reliability (Cronbach’s α = 1). In the validation cohort, the BILDit showed a significant positive correlation with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI; ρ = 0.69; p Conclusions The BILDit seems to be an acceptable and reliable instrument for patient self-evaluation of disease damage, with a good correlation with the SDI. It can be considered as a screening tool for the evaluation of organ damage starting from the patient’s perceptive.

Background Remission or the lowest possible disease activity is the main target in the management of systemic lupus erythematosus (SLE). Anyway, conflicting data are present in the literature regarding the correlation between physician-driven definitions and patient perception of the disease. The objective of this study is to evaluate the relationship between the definition of lupus low disease activity state (LLDAS) and patient’s health-related quality of life (HRQoL). Methods This is a cross-sectional, monocentric study. Adult SLE patients were included. For each patient, demographics, disease duration, medications, comorbidities, organ damage, active disease manifestations and SELENA-SLEDAI were assessed. Patients have been categorised as follows: LLDAS, remission and active disease. Each patient completed the following patient-reported outcomes (PROs): SF-36, LIT, FACIT-Fatigue and SLAQ. A SLAQ score Results We enrolled 259 consecutive SLE patients (mainly female and Caucasian, mean age 45.33 ± 13.14 years, median disease duration 14 years). 80.3% were in LLDAS, of whom 82.2% were in remission; 19.7% were active. No differences emerged for any of the PROs used between the LLDAS and the active group. Considering the LLDAS subgroup, we identified 56 patients with a subjective low disease activity (SLAQ p p p p Conclusions Joint involvement, glucocorticoid therapy and comorbid fibromyalgia resulted to be the most important variables determining the poor concordance between patient and physician perspective on the disease.

ObjectivesTo evaluate the proportion of patients who have successfully withdrawn glucocorticoids (GCs) in a longitudinal cohort of patients with systemic lupus erythematosus (SLE) over a period of 6 years; to evaluate patient characteristics during GC withdrawal in relation to existing definitions of remission and Lupus Low Disease Activity State (LLDAS); and to evaluate the occurrence of flares after GC withdrawal.MethodsPatients who attempted GC withdrawal were identified for the cohort, and the following information was assessed during withdrawal attempts: date of last disease flare, disease activity and damage and ongoing treatment. Information regarding the occurrence of disease flares after GC withdrawal was also recorded for patients who successfully stopped treatment.Definitions of remission were applied to GC withdrawal in line with European consensus criteria (Definitions of remission in SLE [DORIS]) and LLDAS in line with the Asian Pacific Lupus Consortium definition.Results148 patients were involved in the study; GC withdrawal was attempted in 91 patients (61.5%) with 77 patients (84.6%) successfully stopping GCs. At the beginning of the GC reduction, the majority of patients were in complete or clinical remission (48.9% and 39.6%, respectively). Disease activity was significantly lower in patients who successfully stopped GCs, and the proportion of patients in complete remission was higher (54.2%) with respect to patients who failed in their attempt. Among patients who stopped GCs, 18 flares were recorded after a median of 1 year. The time period since the last flare was shorter in patients who experienced flares with respect to patients who did not flare (mean 0.93 years vs 6.0, pConclusionsGC withdrawal is an achievable goal in SLE and may be attempted after a long-term remission or LLDAS to protect the patient from disease flares.

Background: Undifferentiated connective tissue disease (UCTD) is a group of systemic autoimmune conditions which do not fulfil the criteria for a definite connective tissue disease (CTD). The interaction between pregnancy and UCTD is still poorly studied and scarcely recognized. Objectives: The purpose of this study was to evaluate the risk of disease flares or differentiation into a well-defined CTD and also the risk of adverse outcome in pregnancy in patients with UCTD. Methods: A total of 100 pregnancies in 81 UCTD followed at a single center were included in this analysis. From the time the pregnancy was detected, each patient was evaluated every 4 – 6 weeks and the diagnosis was re-evaluated at each observation; the follow-up was considered completed after the last visit during puerperium. At each visit, patients were assessed by a rheumatologist and by a gynecologist. Results: Eleven pregnancies (11%) ended with abortion in the first trimester and the remaining 89 (89%) ended with a live birth. Twelve patients (12%) flared during pregnancy or puerperium and three (3%) had major flares and evolved to systemic lupus erythematosus (SLE) with renal involvement. Obstetric complications were observed in twenty-nine out of the 89 successful pregnancy (33%), including two cases (2%) of preeclampsia. We found a significant association between anti-dsDNA antibodies positivity at baseline and disease flare (p Conclusion: The impact of pregnancy appears to be less serious in UCTD than in other CTDs, however disease flares and obstetric complications can represent a clinical challenge; disease clinical and serological activity seem important determinants of pregnancy outcomes. Thus, a pre-pregnancy counselling and planning as well as a close monitoring during pregnancy is warranted. Disclosure of Interests: Dina Zucchi: None declared, Chiara Tani: None declared, Elena Elefante: None declared, Linda Carli: None declared, Alice Parma: None declared, Francesca Anna Letizia Strigini: None declared, Marta Mosca Paid instructor for: GlaxoSmithKline, Lilly, UCB

Systemic lupus erythematosus (SLE) is an autoimmune connective-tissue disorder with a wide range of clinical manifestations that predominantly affect women. Many aspects of its pathogenesis are still unclear, and new therapeutic strategies are progressively emerging. Thus, in this review we aim to summarise the most relevant data on SLE that emerged during 2018, following the previous annual review of this series. In particular, the review will focus on new insights in SLE regarding new pathogenetic pathways, new biomarkers, new data on clinical manifestations, clinical outcomes and comorbidities and what has emerged on new drugs and new therapeutic strategies.

Background:Over the last decades new therapies have been approved and new treatment strategies have been proposed in the treatment of SLE. In particular, recently, EULAR recommendations1 and the Treat to Target2 approach established a new paradigm for the treatment of SLE based on the early introduction of immunosuppressive treatment and glucocorticoids (GC) minimization.Objectives:to evaluate changes in therapeutic approach and outcomes over the last three decades in a monocentric cohort of SLE patients.Methods:This is a retrospective analysis of prospectively collected data from a monocentric cohort of patients with SLE with disease diagnosis between 1990 and 2020. Based on the year of diagnosis, patients were divided in three groups, each of them corresponding to a decade: group 1: decade 1990-1999; group 2: decade 2000-2009; group 3: decade 2010-2020. For each patient, epidemiological and demographic characteristics, cumulative organ involvement and serology, previous and ongoing therapies, comorbidities were collected and compared among the 3 groups. Organ damage was evaluated by the SLICC-DI (SDI)3 at 1 and 5 years from diagnosis, as comorbidities we considered hypertension, diabetes, osteoporosis and cardiovascular (CV) events occurred during the follow-up.Results:A total of 262 SLE patients were enrolled in the study (97% Caucasian, 90.5% females): 69 patients in group 1, 100 in group 2 and 93 in group 3. Demographic and clinical characteristics of whole cohort and of the three groups are summarized in table 1. Differences in therapies during the first year from diagnosis among the groups are summarized in table 1. In group 3 the use of Micophenolate Mofetil was significantly more common with respect to the group 1 (25% vs 1.4%, p= 0.001) and similar to group 2 (25% vs 25.5%, p=ns); on the contrary, in group 3, Azathioprine (AZA) and Cyclosporine (Cya) were less used (13.2% vs 27.5%, p=0.003 and 3.3% vs 14.3%, p= 0.019 respectively). As Cyclophosphamide (CYC) is concerned, it was used with the same frequency in the three decades, but in group 1, the total dose of CYC was significantly higher than second and third group (4.8 g vs 2.3 and 0.9, p=0.02 and p=0.001 respectively). In group 2 and 3, during the first year of disease, biological drugs (Rituximab or Belimumab) have been used more frequently (2% and 2.2% vs 0%, p=0.04). Any differences have not been showed for GC among the groups. However, in group 3 a significantly higher proportion of patients stopped GC therapy within 5 years from diagnosis (34.5% vs 8.8% and 12.5%, p=0.001) and in the same group the duration of GC therapy was significantly shorter with respect to previous two decades (3.1 years vs 16.8 and 10.5 respectively, p=0.001). As regard damage accrual, at 1 and 5 years from diagnosis, no significant differences among groups were observed; however, hypertension resulted significantly less common in group 3 (10% vs 26% and 37.3%, p=0.001), even adjusting for age (OR=0.2); less CV events were recorded in group 3, but significance is lost adjusting for age.Table 1.Whole cohortGroup 1Group 2Group 3pPatients (n)2626910093Caucasian (%)97%99%98%94.6%.n.s.Females (%)90.5%94.2%95%92.5%n.s.Median age at diagnosis IQR)29 (20-36)27 (20-32)28.5 (20-36)34 (23-44)0.001Cumulative organ involvementRenal48.1%52.2%57%35.5%0.007Articular74.4%75.3%66%82.8%n.s.Serositic19.5%20.3%22%16.1%n.s.Neuropsychiatric8%11.6%6%7.5%n.s.Cutaneous63%70%60%61.3%n.s.Hematological58.4%51.5%61%61.3%n.s.Therapies 1styearAZA17.2%8.7%27.5%13.2%0.003MMF18.7%1.4%25.5%25.3%0.001CYC22.5%21.7%27%17%n.s.Cya9.9%13%14.3%3.30.019Biologicals1.5%0%2%2.2%n.sConclusion:These data show that new therapies and new treatment strategies have actually been implemented in clinical practice over the past 30 years; further studies with a longer follow-up are necessary to appreciate the impact of these advancement on clinical outcomes.References:[1]Bertsias G, et al. Ann Rheum Dis 2008.[2]van Vollenhoven RF, et al.Ann Rheum Dis 2014.[3]Gladman DD, et al. J Rheumatol 2000.Disclosure of Interests:None declared

Background:undifferentiated connective tissue diseases (UCTDs) are a group of systemic autoimmune diseases that share clinical and serological manifestations with definite connective tissue diseases (CTDs), but do not satisfy existing classification criteria1. Within this group, it is possible to identify very heterogeneous conditions: transitory and self-limiting forms, stable conditions over time and forms that will evolve towards definite CTDs, in particular Systemic Lupus Erythematosus (SLE). The availability of new classification criteria for CTDs could be useful in identifying major CTDs from their onset and help in the differentiation from stable UCTDs, which will maintain their undifferentiated profile over time.Objectives:the aim of this study was to apply the new ACR/EULAR 2019 classification criteria of SLE2 to patients included, at the onset of UCTD, to evaluate how many patients could be re-classified as SLE.Methods:this is a retrospective observational study that enrolls patients who received the diagnosis of UCTD at the Rheumatology Unit of Pisa, according to the classification criteria proposed by Mosca et al1, and were then regularly followed in the same clinic (inception cohort). For each patient, demographics, comorbidities, treatment, clinical and serological data were collected, at baseline and during follow-up. The new ACR/EULAR 2019 classification criteria of SLE were applied to the inception cohort at the onset of the disease. The characteristics of patients re-classified as SLE according to the new classification criteria and those of patients who “remained” classified as UCTD were compared.Results:we enrolled 202 patients with a diagnosis of UCTD, mainly female (F:M 193:9) and of Caucasian ethnicity (97.5%), mean age at the diagnosis 38,5 ± 13,2 years and a median follow-up of 5 years (IQR 2-10).During the follow-up, 10 patients (4.9%) in our cohort developed clinical and serological characteristics that led to a diagnosis of a definite CTD, in particular: 7 SLE, 2 Mixed Connective Tissue Disease (MCTD) and 1 Sjogren’s syndrome.Applying the ACR/EULAR 2019 classification criteria of SLE to patients enrolled at the onset of the disease, 38/202 (18.8%) would have been classified as SLE (with a median score of 12 (IQR 11-15)) on the basis of the presenting clinical and serological manifestations. Interestingly, 6/7 patients who received a diagnosis of SLE during the follow-up were among these 38 patients.Among the items of the new classification criteria of SLE, the most frequently satisfied by patients “re-classified” were arthritis (63.2%), hematological (44.7%) and skin (23.7%) manifestations; as for the “immunological” items, hypocomplementemia (71%), SLE-specific (52.6%) and antiphospholipid (35.1%) autoantibodies.Comparing the subgroup of patients “re-classified” as SLE with that of patients who “remained” UCTD, we found that the first group presented more frequently hematological manifestations, hypocomplementemia and anti-dsDNA, anti-Sm, anti-RNP, anti-beta2GPI positivity at the onset of the disease (pConclusion:The development of increasingly sensible and specific classification criteria for definite CTDs may guide in the identification of stable UCTDs since their early stages and consequently in better definition of these conditions that can be considered as a distinct clinical entity.The early identification of stable UCTD is of great importance not only for clinical management (follow-up schedules as well as therapeutic protocols) but also for scientific implications.References:[1]Mosca M. et al., Clin Exp Rheumatol. Sep-Oct 1999;17(5):615-20; 2. Fanouriakis A. et al., Ann Rheum Dis. 2020 Jun;79(6):713-723.Disclosure of Interests:None declared

Background:In SLE pregnancies adverse pregnancy outcomes (APO) are more frequent than in general obstetric population (GOP). In clinical practice, low C3 and C4 levels are associated with active disease and, during pregnancy, complement activation products are shown to be associated with APO.Objectives:To analyse complement variations during SLE pregnancies, focusing on disease flares and APO.Methods:Data on SLE pregnancies prospectively-followed by multidisciplinary team in 2 Italian Centers from 1987 to 2018 were retrospectively analysed. C3 and C4 normal levels were calculated in general obstetric population (GOP) as previously described1, and related to maternal and fetal outcome. Non categorical variables were compared using Mann-Whitney test or Wilcoxon test when appropriate.Results:Two hundred forty-six pregnancies in 172 SLE patients were analysed (mean age at conception 31.3 ±4.9 years; mean disease duration 8.3 ±7.1). Anti-Ro antibodies were positive in 64 patients (37%) and anti-phospholipid antibodies (aPL) were positive in 84 (48%), with single positivity in 54%, double in 24% and triple in 21%; 9 patients (5%) had also a diagnosis of obstetric-antiphospholipid syndrome (APS) and 8 (4%) had thrombotic-APS. Seventy-one patients (41%) had history of Lupus Nephritis.Thirty-five flares were recorded in 30 pregnancies (12%). APO occurred in 47 pregnancies (19%) and were: 27 fetal loss (20 early miscarriage th week and 7 intrauterine fetal death), 11 severe preterm birth (th week) and 15 hypertensive disorder (11 pre-eclampsia and 5 pre-eclampsia+HELLP syndrome).In GOP, C3 progressively increased throughout pregnancy and C4 increase from the 1st trimester to the 2nd trimester, as well as in SLE pregnancies without flares and without APO, from preconception (Fig 1). In the other SLE groups, C3 and C4 showed a different trend: in pregnancies with flares, they did not increase from preconception to the 1st trimester; in fetal losses and severe pre-term births, they remained stable throughout pregnancy; in hypertensive disorders they increased only between preconception and the 1st trimester.C3 and C4 levels were higher in GOP than in all SLE pregnancies groups (including those without flares and without APO) in each trimester. SLE pregnancies without flares showed higher C3 and C4 levels than pregnancies with flares, at preconception and in each trimester. SLE pregnancies without APO had higher C3 and C4 levels than pregnancies with fetal death at 2nd trimester, higher C3 levels than severe pre-term births in each trimester and higher C4 at 3rd trimester (Fig.1).At preconception, pregnancies with flares showed a higher frequency of low C3 and of low C4 than in pregnancies without flares (76% vs 42%, p=0.01; 76% vs 26%, pst: 82% vs 48%, p=0.003; 2nd: 82% vs 64%, p=0.01; 3rd: 64% vs 30%, p=0.002). At multivariate analysis, low C4 at preconception was associated with flare (OR [95% CI]: 10.34 [2.52-42.39]; p=0.001).Figure 1.Variations of C3 and C4 median levels (mg/dL) throughout pregnancy in GOP1 and in SLE pregnancies without and with flare (a) and without and with APO (b).* p ^as compared with SLE groups: pConclusion:In SLE pregnancies, monitoring of C3 and C4 is important: its failure to increase can be useful to recognize potential risk situations which deserve particular monitoring.References:[1]Reggia R. et al. Rheumatology 2012;51:2186-2190.Disclosure of Interests:None declared

Background:The role of complement in the antiphospholipid (aPL) related pathology has been widely studied in animal models. Antiphospholipid antibodies can induce fetal loss in experimental animals but mice deficient in specific complement components (C4, C3, C5) appear somehow protected. In addition, in pregnant mice injected with aPL, antibody deposition has been found at decidual level causing focal necrosis, apoptosis and neutrophil infiltrates and supporting aPL pathogenetic potential. On the other hand, human studies did find hypocomplementemia associated to pregnancy complications in patients with obstetric antiphospholipid syndrome (APS). These results, however, are not unanimously confirmed and, in addition, some studies only show increased levels of complement activation products (i.e. Bb) and not decreased levels of C3 and/or C4. A recently study focusing on complement level in early pregnancy and before pregnancy showed a significant correlation with pregnancy complications and loss in a large cohort of primary APS.Objectives:To investigate if the simple detection of low C3 and/or C4 could be considered a risk factor for adverse pregnancy outcome in APS and aPL carriers pregnancies.Methods:We performed a multicentric study including patients from 10 Italian and 1 Russian Centers. Data on pregnancies in women with primary APS (n=434) and asymptomatic carriers with persistently positive aPL but not fulfilling clinical criteria for APS (n=218) were retrospectively collected. Serum C3 and C4 levels were evaluated by nephelometry; hypocomplementemia was defined by local laboratory reference values. Statistical analysis was performed using GraphPad.Results:Preconceptional complement levels and gestational outcome were available for 107 (25%) pregnancies in APS out of 434 and for 196 (90%) pregnancies in aPL carriers women out of 218. In pregnancies with low preconceptional C3 and/or C4, a significantly higher prevalence of pregnancy losses was observed (p=0.019). A subgroup analysis focusing on triple aPL positive patients was also performed. Preconceptional low C3 and/or C4 levels were found to be associated with an increased rate of pregnancy loss (p = 0.027) in this subgroup also. Otherwise, adverse pregnancy outcomes in single or double aPL positive women were not related to preconception complement levels (p = 0.44) (Table 1). Of note, all the pregnancy losses in the triple positive group occurred in patients treated with low dose aspirin and low molecular weight heparin from the time of positive pregnancy test.Conclusion:Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of adverse outcome. This has been seen only in in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss. test positivity.References:[1]De Carolis S, et al. Complementemia and obstetric outcome in pregnancy with antiphospholipid syndrome. Lupus (2012) 21:776–8.[2]Kim MY, et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis (2018) 77:549–55.[3]Fredi M, et al. Risk Factors for Adverse Maternal and Fetal Outcomes in Women With Confirmed aPL Positivity: Results From a Multicenter Study of 283 Pregnancies. Front Immunol. 2018 May 7;9:864.Triple aPL positivitySingle or double aPL positivityGestational outcomeLow C3/C4 (n=49)Normal C3/C4(n=17)pLow C3/C4 (n=57)Normal C3/C4(n=165)pTerm live birth (>37w)15 (31%)6 (35%)ns34 (60%)110 (67%)nsPreterm live birth (≤37w)22 (45%)11 (65%)ns15 (26%)38 (23%)nsPregnancy losses (abortion and miscarriages)12 (24%)0 (0%)0.0278 (14%) 17 (10%)nsDisclosure of Interests:None declared

Background:Remission or the lowest possible disease activity are the main targets in the management of Systemic Lupus Erythematosus (SLE). Anyway, conflicting data are present in the literature regarding the correlation between physician-driven definitions and patient perception of the disease. The discordance between patient and physician perspectives may have a negative impact on disease outcomes.Objectives:The aim of this study was to identify the main determinants of patient-physician discordance in the evaluation of SLE and health status.Methods:This is a cross-sectional study that enrolls patients with a diagnosis of SLE (ACR 1997 criteria). For each patient, demographics, comorbidities, treatment, clinical and laboratory data were collected. Disease activity was evaluated with the SELENA-SLEDAI score and organ damage with the SLICC/DI. Patients included have been categorized according to the following categories: remission, on or off treatment1, low disease activity (LLDAS)2and active disease status. At enrollment, each patient completed the following PROs: SF-36, FACIT-Fatigue, LIT and SLAQ. We defined a SLAQ scoreResults:We enrolled 259 consecutive adult SLE patients (93.05% female, 97.2% Caucasian, mean age 45.33±13.14 years, median disease duration 14 years (IQR 6-21)). 208/259 patients satisfied the definition of LLDAS and among them 171 were in remission; 51/259 patients were active. No significant differences emerged as for the results of PROs between groups. Considering the subgroup of 208 patients in LLDAS, we identified 56 patients with a subjective condition of low disease activity (SLAQTable 1.Determinants of patient-physician discordanceDiscordant patients(152/208)Concordant patients(56/208)p-valueAge at enrollment(years)47.7±13.144.3±10.8nsDisease duration(years)15.5±10.213.8±9.2nsSLICC-DI1.3±1.70.9±1.7nsOngoing joint involvement(% of patients)10.5%0pPast joint involvement(% of patients)70.9%55.3%pGC therapy(% of patients)50%28.6%pGC daily dose(mg of prednisone)1.6±1.91.1±1.9p=0.06Fibromyalgia(% of patients)15.8%1.8%pPCS54.7±14.165.8±20.4pMCS54±14.564.3±17.7pLIT28.4±20.414±16.8pFACIT35.3±10.147.3±3.6pConclusion:Articular involvement, fibromyalgia and ongoing glucocorticoid treatment, even at low dose, are the major determinants of patient-physician discordance in SLE, determining a negative patient perception of health status.References:[1]van Vollenhoven R, et al. Ann Rheum Dis 2017 - Review. PMID 27884822;[2]Franklyn K, et al. Ann Rheum Dis 2016. PMID 26458737Disclosure of Interests:None declared

BackgroundFatigue is a very common and debilitating symptom in patients with systemic lupus erythematosus (SLE), even among those with a mild or inactive disease. The objective of this study is to define fatigue determinants and describe the impact of fatigue on health-related quality of life (HRQoL) and illness perception in a monocentric cohort of patients with SLE.MethodsThis is a cross-sectional study. Adult patients with SLE were included. For each patient, demographics, medications, comorbidities, organ damage (Systemic Lupus International Collaborating Clinics Damage Index), active disease manifestations and Systemic Lupus Disease Activity Index scores were collected. It was evaluated if each patient met the definitions of remission and low disease activity. At enrolment, each patient completed the Short Form-36 (SF-36), Functional Assessment Chronic Illness Therapy-Fatigue (FACIT-F), Lupus Impact Tracker (LIT), Systemic Lupus Activity Questionnaire (SLAQ) and Brief Index of Lupus Damage (BILD). The FACIT-F questionnaire was also administered to a group of healthy controls.Results223 patients were included (mean age 44.9±13.2 years, median disease duration 13 years). 18.2% had an active disease, 43.5% met the definition of remission on treatment, and 11.8% had a concomitant fibromyalgia. The median FACIT-F score of our cohort was significantly lower compared with that of healthy controls (40 vs 47; pConclusionsFatigue in patients with SLE has a strong negative impact on HRQoL and patient perception of the disease burden. Fatigue seems irrespective of disease activity but significantly influenced by the presence of fibromyalgia.

Systemic lupus erythematosus (SLE) is a systemic autoimmune condition characterised by a wide spectrum of clinical manifestations, partly related to the disease itself, but also linked to its comorbidities and drugs adverse reactions. Following the previous annual reviews, we focused on new insights in SLE clinical features, pathogenic pathways, biomarkers of specific organ involvement and therapeutic strategies. We finally concentrated on SLE aspects that could significantly influence patients' quality of life and that need to be investigated in detail through the development and validation of disease-specific patient-reported outcomes.

ObjectiveTo analyze complement level variations in systemic lupus erythematosus (SLE) pregnancies, focusing on disease flares and obstetric complications.MethodsSLE pregnancies prospectively followed by multidisciplinary teams from 1987 to 2018 in 2 Italian rheumatology centers were retrospectively analyzed. As reference, pregnancy-modified ranges of normal levels of C3 and C4 were derived from 175 pregnancies from the general obstetric population (GOP), as previously described by our group.ResultsTwo hundred forty-six pregnancies in 172 patients with SLE were analyzed. Eighty-nine percent were live births. Thirty-five flares were recorded in 30 pregnancies (12.2%) and obstetric complications occurred in 47 pregnancies (19.1%) including 27 pregnancy losses, 11 severely preterm births (2 resulting in perinatal death), and 15 hypertensive disorders. C3 and C4 levels were higher in the GOP than in patients with SLE, at any time point. C3 and C4 levels progressively increased during pregnancy in both GOP and SLE pregnancies without flare and obstetric complications, whereas this physiological increase was not observed in pregnancies with flares or obstetric complications. A significantly higher frequency of low C4 was found in pregnancies with flares (at preconception and in each trimester) and preterm births (at preconception). In multivariate analysis, low C4 at preconception was associated with flares (odds ratio 13.81, 95% CI 3.10-61.43,P< 0.001).ConclusionLow C4 at preconception was found to be an independent risk factor for SLE flare during pregnancy. Not only C3 and C4 levels but also their variations should be observed, as their failure to increase can be useful to predict risk of complications and suggest closer monitoring.