Background Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial fu... more Background Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial function. In patients with systemic lupus erythematosus (SLE), the numerical reduction and functional impairment of EPCs contribute to the endothelial dysfunction. Through ex vivo and in vitro studies, we aimed at evaluating the effects of B lymphocyte stimulator (BLyS) on EPC colonies and endothelial cells and also investigating BLyS receptor expression on these cells. Methods EPCs were isolated from peripheral blood mononuclear cells (PBMC). In order to evaluate their ability to form colonies, EPCs were cultured on fibronectin-coated dishes and incubated with BlyS alone or BlyS and belimumab. Apoptosis of EPCs and endothelial cell line EA.hy926 was evaluated after 6, 12, and 24 h of incubation with BLyS and after 6 h with BLyS and belimumab. The expression of B cell activating factor-receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator an...
To define the safety and efficacy of TNF inhibitors (TNFi) in RA patients with comorbidities. A N... more To define the safety and efficacy of TNF inhibitors (TNFi) in RA patients with comorbidities. A National Consensus Conference adopted a five-step process to better address the place of TNFi in the treatment of RA. Here we report the work focused on the influence of comorbidities on TNFi efficacy and the effect of TNFi on comorbidities using a Population Intervention Comparison Outcome-based strategy from 8 April 2013 to 15 January 2016. A total of 4453 hits were analysed, of which 10 were eligible for full review. Data show that the presence of comorbidities influences the treatment strategy and several clinical outcomes. The risk of solid cancer is similar in RA patients treated with TNFi or with conventional synthetic DMARDs, and the risk of recurrent breast cancer is not higher in RA patients treated with TNFi. The risk of developing serious infections is higher in RA patients receiving TNFi than conventional synthetic DMARDs. Patients with previous serious infections before star...
The application of more sensitive imaging techniques, such as ultrasonography (US), changed the c... more The application of more sensitive imaging techniques, such as ultrasonography (US), changed the concept of non-erosive arthritis in systemic lupus erythematosus (SLE), underlining the need for biomarkers to identify patients developing the erosive phenotype. Anti-citrullinated peptide antibodies (ACPA), associated with erosions in inflammatory arthritis, have been identified in about 50% of patients with SLE with erosive arthritis. More recently, anti-carbamylated proteins antibodies (anti-CarP) have been associated with erosive damage in rheumatoid arthritis. We aimed to assess the association between anti-CarP and erosive damage in a large SLE cohort with joint involvement. We evaluated 152 patients (male/female patients 11/141; median age 46 years, IQR 16; median disease duration 108 months, IQR 168). All patients underwent blood draw to detect rheumatoid factor (RF) and ACPA (commercial enzyme-linked immunosorbent assay (ELISA) kit), and anti-CarP ("home-made" ELISA, c...
Cognitive impairment (CI) has been described in 3-80% of Systemic lupus erythematosus (SLE) patie... more Cognitive impairment (CI) has been described in 3-80% of Systemic lupus erythematosus (SLE) patients but only short-term studies evaluated its over-time changes, suggesting that CI is usually a stable finding. We aimed at evaluating the changes of SLE-related CI in a 10-years prospective single center cohort study. We evaluated 43 patients (M/F 5/38; mean age = 45.7±10.1 years; mean disease duration = 230.8±74.3 months) at baseline (T0) and after 10 years (T1). A test battery designed to detect fronto-subcortical dysfunction across five domains (memory, attention, abstract reasoning, executive and visuospatial function) was administered. A global cognitive dysfunction score (GCD) was obtained and associated with clinical and laboratory features. Prevalence of CI was 20.9% at T0 and 13.9% at T1 (P = NS). This impairment was prevalently mild at T0 (55.5%) and mild or moderate at T1 (36.3% for both degrees). After 10 years, CI improved in 50% of patients, while 10% worsened. Impaired m...
Autoimmune diseases are a complex set of diseases characterized by immune system activation and, ... more Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet nee...
The increased survival in Systemic Lupus Erythematosus (SLE) patients implies the development of ... more The increased survival in Systemic Lupus Erythematosus (SLE) patients implies the development of chronic damage, occurring in up to 50% of cases. Its prevention is a major goal in the SLE management. We aimed at predicting chronic damage in a large monocentric SLE cohort by using neural networks. We enrolled 413 SLE patients (M/F 30/383; mean age ± SD 46.3±11.9 years; mean disease duration ± SD 174.6 ± 112.1 months). Chronic damage was assessed by the SLICC/ACR Damage Index (SDI). We applied Recurrent Neural Networks (RNNs) as a machine-learning model to predict the risk of chronic damage. The clinical data sequences registered for each patient during the follow-up were used for building and testing the RNNs. At the first visit in the Lupus Clinic, 35.8% of patients had an SDI≥1. For the RNN model, two groups of patients were analyzed: patients with SDI = 0 at the baseline, developing damage during the follow-up (N = 38), and patients without damage (SDI = 0). We created a mathemati...
Background Lupus nephritis (LN) affects up to 60% of patients with systemic lupus erythematosus (... more Background Lupus nephritis (LN) affects up to 60% of patients with systemic lupus erythematosus (SLE), either as the initial manifestation or during the disease course. Moreover, LN has a negative impact on survival of SLE patients. Accordingly, it is mandatory to identify specific and feasible markers able to guide clinicians towards the adequate therapeutic option in LN patients. Recently, a significant correlation between pathologic Resistive Index (RI) and class IV nephritis was identified, suggesting a role for RI as a severity marker. Objectives We aimed at evaluating the role of RI as a marker of activity in a large cohort of LN patients. Methods Consecutive patients with SLE who required a kidney biopsy were enrolled. SLE patients with known renal artery stenosis, heart failure, hepatic diseases and urinary tract obstruction were excluded. Functional renal evaluation was performed by assessing serum creatinine (mg/dL), blood urea nitrogen (BUN, mg/dL) and daily urinary protein excretion (g/24 h). Moreover, the estimated glomerular filtration rate (eGFR, mL/min) was assessed by using the formula developed by the Modification of Diet in Renal Disease Study. Immediately before renal biopsy, the ultrasonography evaluation was performed to assess RI (Aplio Ultrasound System SSA-790; convex probe 3.5-MHz, Toshiba, Tokyo, Japan). An RI value >0.7 was considered pathologic. The histologic characteristics of each kidney biopsy were registered in accordance with the International Society of Nephrology/Renal Pathology (ISN/RPS) Classification. Finally, biopsy-based activity (range: 0–24) and chronicity (range: 0–12) indices were calculated. Results Sixty patients (M/F 4/56; mean age 35.3±11.3 years; mean disease duration 150.0±90.0 months) underwent kidney biopsy. According with ISN/RPS classification, 29 (48.3%) patients had a class IV, 17 (28.3%) a class III, 8 (13.4%) a class II, and 6 (10.0%) a class V LN. Seven patients (11.7%) showed an RI>0.7: one had a class III and 6/7 (85.7%) had a class IV. The evaluation of the activity index demonstrated the presence of significant higher values in patients with an RI>0.7 compared with those with normal RI values (8.6±5.0 versus 4.2±3.9; P=0.03). Moreover, RI values significantly correlated with age (P=0.01; R=0.3), creatinine levels (P=0.005; R=0.3), BUN (P=0.02; R=0.2), and eGFR (P=0.006; R=-0.3). Conclusions In the present study, a significant association between pathologic RI and histological activity index in LN patients was found. In addition, we identified an association between pathological RI and a more severe kidney involvement suggesting a role of RI as an activity and severity marker of LN. Disclosure of Interest None declared
Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a ... more Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a wide range of clinical manifestations and by a typically fluctuant course. Although SLE patients' survival has significantly increased in the last decades, morbidity and hospitalization are still considerably high. Objectives Aim of this study was to analyze seasonality, causes and outcome of SLE patients' hospitalization in a tertiary centre over a 10-years period. Methods We conducted a retrospective analysis of all the admissions to the Rheumatology Unit in a period of 10 years; we used hospital registries as a source of causes and time of hospitalization. The analysis was then restricted on SLE patients: we collected demographic, clinical and serological features. In particular, we investigated the frequency and causes of hospitalization, the seasonality and mortality. We evaluated disease activity through SLE Disease Activity Index-2000 (SLEDAI-2K), and chronic damage by the SLICC Damage Index (SDI). Results Between January 2003 and December 2013, we admitted to our Rheumatology Unit 1615 patients: 315 (19.5%) were SLE patients (M/F 35/280; mean ± SD age 38.5±12.3 years; mean ± SD disease duration 135.2±99.7 months). The mean ± SD time of hospital stay was 15.4±17.8 days. Disease flare was the most frequent cause of hospitalization, recorded in 66.7% of SLE patients, followed by infections (12.4%), active lupus nephritis for renal biopsy (9.3%), infusional therapies (4.5%), drugs adverse events (1.4%), cancer (0.6%) and cardiovascular accident (0.3%), other (4.8%). The frequency of disease flare was significantly higher than all the other causes of hospital admittance [P<0.000001]. Mortality rate was 0.3%. As for seasonality (in the boreal hemisphere), most of SLE patients were admitted in May (12.4%), January (10.8%) and September (10.5%), without any significant difference among the seasons. Considering SLE patients' admissions for flare compared to the other causes, we did not find any significant differences in seasonality. The evaluation of disease activity was available for 194 patients and we recorded a median SLEDAI-2K value of 8 (IQR 5.5) and a median SDI value of 1 (IQR 1) at the time of admission. As expected, SLE patients admitted for flare showed a significantly higher SLEDAI-2K value than those admitted for infections (P=0.02). Conclusions This retrospective analysis of all the hospitalizations in a Rheumatology Unit over a period of 10 years has showed that SLE patients' admissions are frequent and that SLE flare is the most frequent cause of hospitalization. Moreover, it has showed a low incidence of death during the hospital stay. Finally, it has registered that May was the most frequent admission month and it has not found any significant differences in seasonality between SLE flare and other causes of hospitalization. Disclosure of Interest None declared
Background Renal involvement in antiphospholipid syndrome (APS) is still relatively unknown and p... more Background Renal involvement in antiphospholipid syndrome (APS) is still relatively unknown and probably underestimated. The main lesions consist of renal artery stenosis (RAS), venous renal thrombosis, and glomerular lesions. The resistive index (RI) of intra-renal arteries, indicating vascular resistance, has been evaluated in different nephropathies showing an association with functional parameters and histological features. Nonetheless, there are no studies in patients with APS. Objectives We aimed to evaluate the renal arteries RI, by color-Doppler ultrasonography (US), in a group of patients affected by APS. Methods We enrolled patients with primary APS (PAPS-Sapporo revised criteria), patients with APS secondary to Systemic Lupus Erythematosus (SAPS-1997 ACR criteria) and subjects positive for antiphospholipid antibodies without clinical manifestations (aPL-carriers). All patients underwent clinical assessment (anamnestic data and traditional risk factors for cardiovascular disease), and laboratory evaluation (anti-cardiolipin, anti-β2 glycoprotein I, lupus anticoagulant, C3 and C4 serum levels). US Doppler assessment was performed, RI>0.7 was considered pathologic. Results We enrolled 11 patients with PAPS, 22 patients with SAPS and 11 aPL-carriers. The clinical and laboratory features are described in Table. Pathologic RI was detected in 27.3% of SAPS patients compared to 9.1% of PAPS and aPL-carriers (P=NS). A significant correlation between the mean RI and the presence of hypertension (Spearman's test P<0.001, r=0.838) and diabetes (P<0.001, r=0.861) was observed in PAPS patients. Interestingly, RAS was observed only in patients with PAPS (3/11, 27.3%) and in none of SAPS and aPL-carriers. Finally, the presence of stenosis was not associated with a pathologic RI. Table 1 SAPS (n=22) PAPS (n=11) APL (n=11) P Sex (M/F) 2/20 5/6 5/6 PAPS & APL vs SAPS 0.027 Mean age, years (mean ± SD) 43.45±12.19 40.91±14 43.63±14.34 NS Disease duration, months (mean ± SD) 123.3±62.43 57.82±34.7 NA 0.003 Hypertension (n/%) 9 (40.9%) 6 (54.5%) 2 (18.2%) NS C3 <80 mg/dl (n/%) 9 (40.9%) 2 (18.2%) 1 (9.1%) NS C4 <15 mg/dl (n/%) 7 (31.8%) 3 (27.3%) 1 (9.1%) NS Diabetes (n/%) 1 (4.5%) 1 (9.1%) 1 (9.1%) NS Smoke (n/%) 4 (18.2%) 0 2 (19.2%) NS Hyperlipidemia (n/%) 4 (18.2%) 1 (9.1%) 0 NS Body mass index (mean ± SD) 24.73±5.14 25.87±2.85 24.46±3.38 NS Stenosis (n/%) 0 3 (27.3%) 0 SAPS vs PAPS 0.03 Mean RI (mean ± SD) 0.65±0.06 0.66±0.06 0.64±0.06 NS Mean RI >0.7 (n/%) 6 (27.3%) 1 (9.1%) 1 (9.1%) NS anti-cardiolipin (n/%) 22 (100%) 9 (81.8%) 7 (63.6%) NS Lupus anticoagulant (n/%) 11 (50%) 6 (54.5%) 6 (54.5%) NS Anti-b2 glycoprotein I (n/%) 13 (59.1%) 9 (81.8%) 7 (63.6%) NS Conclusions We evaluated for the first time the intra-renal artery RI in APS patients: a pathological RI was detected mostly in SAPS patients. Conversely, RAS was detected only in PAPS patients. These results could suggest a different diathesis in the pathogenesis of the renal vascular manifestations in patients with APS. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5631
Background Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells able to ... more Background Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells able to differentiate into mature endothelial cells; impairment of number and function of these cells is associated with increased subclinical atherosclerosis. Cardiovascular risk is highly increased in patients with Systemic Lupus Erythematosus (SLE). Several studies demonstrated that EPCs are reduced and impaired in SLE patients, partially accounting for the endothelial dysfunction characterizing these patients. In murine models, the inhibition of B Lymphocyte Stimulator (BLyS) was associated to a reduction of atherosclerotic plaque. In vivo effect of Belimumab, a monoclonal antibody targeting BLyS, on atherosclerotic process has not been yet addressed. Objectives Aim of the study was to assess the short-term effect of Belimumab treatment on EPC number in SLE patients. Methods We enrolled consecutive patients with SLE diagnosed according to 1997 ACR criteria due to start Belimumab for unresponsiveness to standard therapy. Patients with known cardiovascular disease were excluded. As control, we studied age and sex-matched healthy subjects. SLE disease activity was evaluated by SLEDAI 2K at baseline and after 4 and 12 weeks of Belimumab treatment. Blood samples were collected at the same time-point in heparinized vials. Blood samples from healthy subjects were collected on the same day of baseline patients' visit. Peripheral blood mononuclear cells (PBMCs) were incubated with fluorescein isothiocyanate-labeled anti-CD34 monoclonal antibodies and phycoerythrin-labeled anti VEGF-R2/KDR; acquisition was performed by flow cytometry. EPCs were defined as CD34/KDR double-positive cells. Kolmogorov-Smirnov showed the normal distribution of EPCs; data were expressed as mean ± standard deviation. To test the hypothesis that Belimumab may increase EPCs number we used one-tailed T-test. A p value <0.05 was considered statistically significant. Results We enrolled 7 female patients (age 45.6±11.2 yrs, disease duration 17.8±10.8 yrs) with active disease (mean baseline SLEDAI 8.4±2.6). After 4 and 12 weeks we observed a trend in disease activity reduction (p=ns). Baseline EPC mean number was significantly lower in SLE patients compared to healthy subjects (0.072 ± 0.004 vs 0,025 + 0.02, p=0.01). At week 4, the mean number of EPC increased to 0.019 ± 0.02 (p=0.025 vs baseline; p=n.s. vs NHS); at week 12 we did not observe any difference compared to baseline nor week 4. We did not find a correlation between SLEDAI and EPCs number at any time-point. Conclusions The results of our pilot study demonstrate, for the first time, the short-term effect of Belimumab on EPC number in SLE patients. Several studies in mouse models established a role for B cells in atherosclerosis. Anti-BLyS could act by selectively depleting B2 cells, a sub-population of B lymphocytes with pro-atherogenic properties or, indirectly, by modulating other pro-inflammatory cytokines as well as Th17 cells, involved in the atherosclerotic process. Disclosure of Interest None declared
The definition of posttranslational modification (PTM) encompasses a wide group of chemical react... more The definition of posttranslational modification (PTM) encompasses a wide group of chemical reactions that allow modification and modulation of protein functions. The regulation of PTMs is crucial for the activity and survival of the cells. Dysregulation of PTMs has been observed in several pathological conditions, including rheumatoid arthritis (RA). RA is a systemic autoimmune disease primarily targeting the joints. The three PTMs mainly involved in this disease are glycosylation, citrullination, and carbamylation. Glycosylation is essential for antigen processing and presentation and can modulate immunoglobulin activity. Citrullination of self-antigens is strongly associated with RA, as demonstrated by the presence of antibodies directed to anti-citrullinated proteins in patients’ sera. Carbamylation and its dysregulation have been recently associated with RA. Aim of this review is to illustrate the most significant alterations of these PTMs in RA and to evaluate their possible i...
Objectives. The anti-dsDNA antibodies are a marker for Systemic Lupus Erythematosus (SLE) and 70–... more Objectives. The anti-dsDNA antibodies are a marker for Systemic Lupus Erythematosus (SLE) and 70–98% of patients test positive. We evaluated the demographic, clinical, laboratory, and therapeutical features of a monocentric SLE cohort according to the anti-dsDNA status.Methods. We identified three groups: anti-dsDNA + (persistent positivity); anti-dsDNA ± (initial positivity and subsequent negativity during disease course); anti-dsDNA − (persistent negativity). Disease activity was assessed by the European Consensus Lupus Activity Measurement (ECLAM).Results. We evaluated 393 patients (anti-dsDNA +: 62.3%; anti-dsDNA ±: 13.3%; anti-dsDNA −: 24.4%). The renal involvement was significantly more frequent in anti-dsDNA + (30.2%), compared with anti-dsDNA ± and anti-dsDNA − (21.1% and 18.7%, resp.;P=0.001). Serositis resulted significantly more frequent in anti-dsDNA − (82.3%) compared to anti-dsDNA + and anti-dsDNA ± (20.8% and 13.4%, resp.;P<0.0001). The reduction of C4 serum levels...
The assessment of disease activity in patients affected by Systemic Lupus Erythematosus (SLE) rep... more The assessment of disease activity in patients affected by Systemic Lupus Erythematosus (SLE) represents an important issue, as recommended by the European League Against Rheumatism (EULAR). Two main types of disease activity measure have been proposed: the global score systems, providing an overall measure of activity, and the individual organ/system assessment scales, assessing disease activity in different organs. All the activity indices included both clinical and laboratory items, related to the disease manifestations. However, there is no gold standard to measure disease activity in patients affected by SLE. In this review, we will analyze the lights and shadows of the disease activity indices, by means of a critical approach. In particular, we will focus on SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), the most frequently used in randomized controlled trials and observational studies. The evaluation of data from the literature underlined some limitations of these indices, making their application in clinical practice difficult and suggesting the possible use of specific tools in the different subset of SLE patients, in order to capture all the disease features.
Objectives. To evaluate the application of Disease Activity Score 28 (DAS28) to assess joint invo... more Objectives. To evaluate the application of Disease Activity Score 28 (DAS28) to assess joint involvement in Systemic Lupus Erythematosus (SLE).Methods. Sixty-nine SLE patients, complaining of joint symptoms, and 44 rheumatoid arthritis (RA) patients were enrolled. In SLE patients disease activity was assessed with SLEDAI-2K. DAS28 was calculated in all the patients.Results. Thirty SLE patients (43.5%) showed clinical signs of arthritis. Mean DAS28 was4.0±1.4, 22 patients (31.9%) had low disease activity, 29 (42.0%) moderate, and 18 (26.1%) high. We dichotomized SLE patients according to the presence (Group 1) or absence (Group 2) of articular involvement according to SLEDAI-2K: 56.3% of the patients of the second group had a moderate/high activity according to DAS28. We compared SLE patients with 44 RA patients (M/F 9/35, mean age55.6±14.5years; mean disease duration140.4±105.6months). No significant differences were found regarding the values of DAS28 between SLE and RA patients. O...
In the present study, we performed a retrospective study on the indication, efficacy and causes o... more In the present study, we performed a retrospective study on the indication, efficacy and causes of withdrawal of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE). Moreover, a review of the literature concerning the use of MMF in the real life was performed. We recorded data about indications, mean dosage, duration of treatment and reasons for drug withdrawal. The efficacy was evaluated according to changes in SLE Disease Activity Index 2000 (SLEDAI-2K), renal SLEDAI-2K and daily proteinuria, after 4 and 12 months of treatment. Six hundred and nine SLE patients were evaluated; among them, 109 patients (17.9 %) were treated with MMF (mean treatment duration 33.9 ± 31.2 months, mean dosage 28.1 ± 10.6 mg/kg). The most frequent indications for using MMF were lupus nephritis (55.9 %) and musculoskeletal manifestations (33.0 %). After 4 and 12 months, a significant reduction of mean SLEDAI-2K, renal SLEDAI and daily proteinuria, compared with baseline, was demonstrated. Thirty-one patients (28.4 %) discontinued MMF therapy (mean treatment duration at the time of discontinuation 17.5 ± 21.2 months). The incidence risks of MMF discontinuation due to inefficacy and side effects were 0.09 and 0.1, respectively. Patients with disease duration longer than 36 months (70.6 %) had a significant increased risk of MMF withdrawal (RR 0.4, P = 0.03). The results of the present study demonstrated that MMF should be considered a treatment option for SLE manifestation other than renal involvement in daily clinical practice.
Background Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial fu... more Background Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial function. In patients with systemic lupus erythematosus (SLE), the numerical reduction and functional impairment of EPCs contribute to the endothelial dysfunction. Through ex vivo and in vitro studies, we aimed at evaluating the effects of B lymphocyte stimulator (BLyS) on EPC colonies and endothelial cells and also investigating BLyS receptor expression on these cells. Methods EPCs were isolated from peripheral blood mononuclear cells (PBMC). In order to evaluate their ability to form colonies, EPCs were cultured on fibronectin-coated dishes and incubated with BlyS alone or BlyS and belimumab. Apoptosis of EPCs and endothelial cell line EA.hy926 was evaluated after 6, 12, and 24 h of incubation with BLyS and after 6 h with BLyS and belimumab. The expression of B cell activating factor-receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator an...
To define the safety and efficacy of TNF inhibitors (TNFi) in RA patients with comorbidities. A N... more To define the safety and efficacy of TNF inhibitors (TNFi) in RA patients with comorbidities. A National Consensus Conference adopted a five-step process to better address the place of TNFi in the treatment of RA. Here we report the work focused on the influence of comorbidities on TNFi efficacy and the effect of TNFi on comorbidities using a Population Intervention Comparison Outcome-based strategy from 8 April 2013 to 15 January 2016. A total of 4453 hits were analysed, of which 10 were eligible for full review. Data show that the presence of comorbidities influences the treatment strategy and several clinical outcomes. The risk of solid cancer is similar in RA patients treated with TNFi or with conventional synthetic DMARDs, and the risk of recurrent breast cancer is not higher in RA patients treated with TNFi. The risk of developing serious infections is higher in RA patients receiving TNFi than conventional synthetic DMARDs. Patients with previous serious infections before star...
The application of more sensitive imaging techniques, such as ultrasonography (US), changed the c... more The application of more sensitive imaging techniques, such as ultrasonography (US), changed the concept of non-erosive arthritis in systemic lupus erythematosus (SLE), underlining the need for biomarkers to identify patients developing the erosive phenotype. Anti-citrullinated peptide antibodies (ACPA), associated with erosions in inflammatory arthritis, have been identified in about 50% of patients with SLE with erosive arthritis. More recently, anti-carbamylated proteins antibodies (anti-CarP) have been associated with erosive damage in rheumatoid arthritis. We aimed to assess the association between anti-CarP and erosive damage in a large SLE cohort with joint involvement. We evaluated 152 patients (male/female patients 11/141; median age 46 years, IQR 16; median disease duration 108 months, IQR 168). All patients underwent blood draw to detect rheumatoid factor (RF) and ACPA (commercial enzyme-linked immunosorbent assay (ELISA) kit), and anti-CarP ("home-made" ELISA, c...
Cognitive impairment (CI) has been described in 3-80% of Systemic lupus erythematosus (SLE) patie... more Cognitive impairment (CI) has been described in 3-80% of Systemic lupus erythematosus (SLE) patients but only short-term studies evaluated its over-time changes, suggesting that CI is usually a stable finding. We aimed at evaluating the changes of SLE-related CI in a 10-years prospective single center cohort study. We evaluated 43 patients (M/F 5/38; mean age = 45.7±10.1 years; mean disease duration = 230.8±74.3 months) at baseline (T0) and after 10 years (T1). A test battery designed to detect fronto-subcortical dysfunction across five domains (memory, attention, abstract reasoning, executive and visuospatial function) was administered. A global cognitive dysfunction score (GCD) was obtained and associated with clinical and laboratory features. Prevalence of CI was 20.9% at T0 and 13.9% at T1 (P = NS). This impairment was prevalently mild at T0 (55.5%) and mild or moderate at T1 (36.3% for both degrees). After 10 years, CI improved in 50% of patients, while 10% worsened. Impaired m...
Autoimmune diseases are a complex set of diseases characterized by immune system activation and, ... more Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet nee...
The increased survival in Systemic Lupus Erythematosus (SLE) patients implies the development of ... more The increased survival in Systemic Lupus Erythematosus (SLE) patients implies the development of chronic damage, occurring in up to 50% of cases. Its prevention is a major goal in the SLE management. We aimed at predicting chronic damage in a large monocentric SLE cohort by using neural networks. We enrolled 413 SLE patients (M/F 30/383; mean age ± SD 46.3±11.9 years; mean disease duration ± SD 174.6 ± 112.1 months). Chronic damage was assessed by the SLICC/ACR Damage Index (SDI). We applied Recurrent Neural Networks (RNNs) as a machine-learning model to predict the risk of chronic damage. The clinical data sequences registered for each patient during the follow-up were used for building and testing the RNNs. At the first visit in the Lupus Clinic, 35.8% of patients had an SDI≥1. For the RNN model, two groups of patients were analyzed: patients with SDI = 0 at the baseline, developing damage during the follow-up (N = 38), and patients without damage (SDI = 0). We created a mathemati...
Background Lupus nephritis (LN) affects up to 60% of patients with systemic lupus erythematosus (... more Background Lupus nephritis (LN) affects up to 60% of patients with systemic lupus erythematosus (SLE), either as the initial manifestation or during the disease course. Moreover, LN has a negative impact on survival of SLE patients. Accordingly, it is mandatory to identify specific and feasible markers able to guide clinicians towards the adequate therapeutic option in LN patients. Recently, a significant correlation between pathologic Resistive Index (RI) and class IV nephritis was identified, suggesting a role for RI as a severity marker. Objectives We aimed at evaluating the role of RI as a marker of activity in a large cohort of LN patients. Methods Consecutive patients with SLE who required a kidney biopsy were enrolled. SLE patients with known renal artery stenosis, heart failure, hepatic diseases and urinary tract obstruction were excluded. Functional renal evaluation was performed by assessing serum creatinine (mg/dL), blood urea nitrogen (BUN, mg/dL) and daily urinary protein excretion (g/24 h). Moreover, the estimated glomerular filtration rate (eGFR, mL/min) was assessed by using the formula developed by the Modification of Diet in Renal Disease Study. Immediately before renal biopsy, the ultrasonography evaluation was performed to assess RI (Aplio Ultrasound System SSA-790; convex probe 3.5-MHz, Toshiba, Tokyo, Japan). An RI value >0.7 was considered pathologic. The histologic characteristics of each kidney biopsy were registered in accordance with the International Society of Nephrology/Renal Pathology (ISN/RPS) Classification. Finally, biopsy-based activity (range: 0–24) and chronicity (range: 0–12) indices were calculated. Results Sixty patients (M/F 4/56; mean age 35.3±11.3 years; mean disease duration 150.0±90.0 months) underwent kidney biopsy. According with ISN/RPS classification, 29 (48.3%) patients had a class IV, 17 (28.3%) a class III, 8 (13.4%) a class II, and 6 (10.0%) a class V LN. Seven patients (11.7%) showed an RI>0.7: one had a class III and 6/7 (85.7%) had a class IV. The evaluation of the activity index demonstrated the presence of significant higher values in patients with an RI>0.7 compared with those with normal RI values (8.6±5.0 versus 4.2±3.9; P=0.03). Moreover, RI values significantly correlated with age (P=0.01; R=0.3), creatinine levels (P=0.005; R=0.3), BUN (P=0.02; R=0.2), and eGFR (P=0.006; R=-0.3). Conclusions In the present study, a significant association between pathologic RI and histological activity index in LN patients was found. In addition, we identified an association between pathological RI and a more severe kidney involvement suggesting a role of RI as an activity and severity marker of LN. Disclosure of Interest None declared
Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a ... more Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a wide range of clinical manifestations and by a typically fluctuant course. Although SLE patients' survival has significantly increased in the last decades, morbidity and hospitalization are still considerably high. Objectives Aim of this study was to analyze seasonality, causes and outcome of SLE patients' hospitalization in a tertiary centre over a 10-years period. Methods We conducted a retrospective analysis of all the admissions to the Rheumatology Unit in a period of 10 years; we used hospital registries as a source of causes and time of hospitalization. The analysis was then restricted on SLE patients: we collected demographic, clinical and serological features. In particular, we investigated the frequency and causes of hospitalization, the seasonality and mortality. We evaluated disease activity through SLE Disease Activity Index-2000 (SLEDAI-2K), and chronic damage by the SLICC Damage Index (SDI). Results Between January 2003 and December 2013, we admitted to our Rheumatology Unit 1615 patients: 315 (19.5%) were SLE patients (M/F 35/280; mean ± SD age 38.5±12.3 years; mean ± SD disease duration 135.2±99.7 months). The mean ± SD time of hospital stay was 15.4±17.8 days. Disease flare was the most frequent cause of hospitalization, recorded in 66.7% of SLE patients, followed by infections (12.4%), active lupus nephritis for renal biopsy (9.3%), infusional therapies (4.5%), drugs adverse events (1.4%), cancer (0.6%) and cardiovascular accident (0.3%), other (4.8%). The frequency of disease flare was significantly higher than all the other causes of hospital admittance [P<0.000001]. Mortality rate was 0.3%. As for seasonality (in the boreal hemisphere), most of SLE patients were admitted in May (12.4%), January (10.8%) and September (10.5%), without any significant difference among the seasons. Considering SLE patients' admissions for flare compared to the other causes, we did not find any significant differences in seasonality. The evaluation of disease activity was available for 194 patients and we recorded a median SLEDAI-2K value of 8 (IQR 5.5) and a median SDI value of 1 (IQR 1) at the time of admission. As expected, SLE patients admitted for flare showed a significantly higher SLEDAI-2K value than those admitted for infections (P=0.02). Conclusions This retrospective analysis of all the hospitalizations in a Rheumatology Unit over a period of 10 years has showed that SLE patients' admissions are frequent and that SLE flare is the most frequent cause of hospitalization. Moreover, it has showed a low incidence of death during the hospital stay. Finally, it has registered that May was the most frequent admission month and it has not found any significant differences in seasonality between SLE flare and other causes of hospitalization. Disclosure of Interest None declared
Background Renal involvement in antiphospholipid syndrome (APS) is still relatively unknown and p... more Background Renal involvement in antiphospholipid syndrome (APS) is still relatively unknown and probably underestimated. The main lesions consist of renal artery stenosis (RAS), venous renal thrombosis, and glomerular lesions. The resistive index (RI) of intra-renal arteries, indicating vascular resistance, has been evaluated in different nephropathies showing an association with functional parameters and histological features. Nonetheless, there are no studies in patients with APS. Objectives We aimed to evaluate the renal arteries RI, by color-Doppler ultrasonography (US), in a group of patients affected by APS. Methods We enrolled patients with primary APS (PAPS-Sapporo revised criteria), patients with APS secondary to Systemic Lupus Erythematosus (SAPS-1997 ACR criteria) and subjects positive for antiphospholipid antibodies without clinical manifestations (aPL-carriers). All patients underwent clinical assessment (anamnestic data and traditional risk factors for cardiovascular disease), and laboratory evaluation (anti-cardiolipin, anti-β2 glycoprotein I, lupus anticoagulant, C3 and C4 serum levels). US Doppler assessment was performed, RI>0.7 was considered pathologic. Results We enrolled 11 patients with PAPS, 22 patients with SAPS and 11 aPL-carriers. The clinical and laboratory features are described in Table. Pathologic RI was detected in 27.3% of SAPS patients compared to 9.1% of PAPS and aPL-carriers (P=NS). A significant correlation between the mean RI and the presence of hypertension (Spearman's test P<0.001, r=0.838) and diabetes (P<0.001, r=0.861) was observed in PAPS patients. Interestingly, RAS was observed only in patients with PAPS (3/11, 27.3%) and in none of SAPS and aPL-carriers. Finally, the presence of stenosis was not associated with a pathologic RI. Table 1 SAPS (n=22) PAPS (n=11) APL (n=11) P Sex (M/F) 2/20 5/6 5/6 PAPS & APL vs SAPS 0.027 Mean age, years (mean ± SD) 43.45±12.19 40.91±14 43.63±14.34 NS Disease duration, months (mean ± SD) 123.3±62.43 57.82±34.7 NA 0.003 Hypertension (n/%) 9 (40.9%) 6 (54.5%) 2 (18.2%) NS C3 <80 mg/dl (n/%) 9 (40.9%) 2 (18.2%) 1 (9.1%) NS C4 <15 mg/dl (n/%) 7 (31.8%) 3 (27.3%) 1 (9.1%) NS Diabetes (n/%) 1 (4.5%) 1 (9.1%) 1 (9.1%) NS Smoke (n/%) 4 (18.2%) 0 2 (19.2%) NS Hyperlipidemia (n/%) 4 (18.2%) 1 (9.1%) 0 NS Body mass index (mean ± SD) 24.73±5.14 25.87±2.85 24.46±3.38 NS Stenosis (n/%) 0 3 (27.3%) 0 SAPS vs PAPS 0.03 Mean RI (mean ± SD) 0.65±0.06 0.66±0.06 0.64±0.06 NS Mean RI >0.7 (n/%) 6 (27.3%) 1 (9.1%) 1 (9.1%) NS anti-cardiolipin (n/%) 22 (100%) 9 (81.8%) 7 (63.6%) NS Lupus anticoagulant (n/%) 11 (50%) 6 (54.5%) 6 (54.5%) NS Anti-b2 glycoprotein I (n/%) 13 (59.1%) 9 (81.8%) 7 (63.6%) NS Conclusions We evaluated for the first time the intra-renal artery RI in APS patients: a pathological RI was detected mostly in SAPS patients. Conversely, RAS was detected only in PAPS patients. These results could suggest a different diathesis in the pathogenesis of the renal vascular manifestations in patients with APS. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5631
Background Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells able to ... more Background Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells able to differentiate into mature endothelial cells; impairment of number and function of these cells is associated with increased subclinical atherosclerosis. Cardiovascular risk is highly increased in patients with Systemic Lupus Erythematosus (SLE). Several studies demonstrated that EPCs are reduced and impaired in SLE patients, partially accounting for the endothelial dysfunction characterizing these patients. In murine models, the inhibition of B Lymphocyte Stimulator (BLyS) was associated to a reduction of atherosclerotic plaque. In vivo effect of Belimumab, a monoclonal antibody targeting BLyS, on atherosclerotic process has not been yet addressed. Objectives Aim of the study was to assess the short-term effect of Belimumab treatment on EPC number in SLE patients. Methods We enrolled consecutive patients with SLE diagnosed according to 1997 ACR criteria due to start Belimumab for unresponsiveness to standard therapy. Patients with known cardiovascular disease were excluded. As control, we studied age and sex-matched healthy subjects. SLE disease activity was evaluated by SLEDAI 2K at baseline and after 4 and 12 weeks of Belimumab treatment. Blood samples were collected at the same time-point in heparinized vials. Blood samples from healthy subjects were collected on the same day of baseline patients' visit. Peripheral blood mononuclear cells (PBMCs) were incubated with fluorescein isothiocyanate-labeled anti-CD34 monoclonal antibodies and phycoerythrin-labeled anti VEGF-R2/KDR; acquisition was performed by flow cytometry. EPCs were defined as CD34/KDR double-positive cells. Kolmogorov-Smirnov showed the normal distribution of EPCs; data were expressed as mean ± standard deviation. To test the hypothesis that Belimumab may increase EPCs number we used one-tailed T-test. A p value <0.05 was considered statistically significant. Results We enrolled 7 female patients (age 45.6±11.2 yrs, disease duration 17.8±10.8 yrs) with active disease (mean baseline SLEDAI 8.4±2.6). After 4 and 12 weeks we observed a trend in disease activity reduction (p=ns). Baseline EPC mean number was significantly lower in SLE patients compared to healthy subjects (0.072 ± 0.004 vs 0,025 + 0.02, p=0.01). At week 4, the mean number of EPC increased to 0.019 ± 0.02 (p=0.025 vs baseline; p=n.s. vs NHS); at week 12 we did not observe any difference compared to baseline nor week 4. We did not find a correlation between SLEDAI and EPCs number at any time-point. Conclusions The results of our pilot study demonstrate, for the first time, the short-term effect of Belimumab on EPC number in SLE patients. Several studies in mouse models established a role for B cells in atherosclerosis. Anti-BLyS could act by selectively depleting B2 cells, a sub-population of B lymphocytes with pro-atherogenic properties or, indirectly, by modulating other pro-inflammatory cytokines as well as Th17 cells, involved in the atherosclerotic process. Disclosure of Interest None declared
The definition of posttranslational modification (PTM) encompasses a wide group of chemical react... more The definition of posttranslational modification (PTM) encompasses a wide group of chemical reactions that allow modification and modulation of protein functions. The regulation of PTMs is crucial for the activity and survival of the cells. Dysregulation of PTMs has been observed in several pathological conditions, including rheumatoid arthritis (RA). RA is a systemic autoimmune disease primarily targeting the joints. The three PTMs mainly involved in this disease are glycosylation, citrullination, and carbamylation. Glycosylation is essential for antigen processing and presentation and can modulate immunoglobulin activity. Citrullination of self-antigens is strongly associated with RA, as demonstrated by the presence of antibodies directed to anti-citrullinated proteins in patients’ sera. Carbamylation and its dysregulation have been recently associated with RA. Aim of this review is to illustrate the most significant alterations of these PTMs in RA and to evaluate their possible i...
Objectives. The anti-dsDNA antibodies are a marker for Systemic Lupus Erythematosus (SLE) and 70–... more Objectives. The anti-dsDNA antibodies are a marker for Systemic Lupus Erythematosus (SLE) and 70–98% of patients test positive. We evaluated the demographic, clinical, laboratory, and therapeutical features of a monocentric SLE cohort according to the anti-dsDNA status.Methods. We identified three groups: anti-dsDNA + (persistent positivity); anti-dsDNA ± (initial positivity and subsequent negativity during disease course); anti-dsDNA − (persistent negativity). Disease activity was assessed by the European Consensus Lupus Activity Measurement (ECLAM).Results. We evaluated 393 patients (anti-dsDNA +: 62.3%; anti-dsDNA ±: 13.3%; anti-dsDNA −: 24.4%). The renal involvement was significantly more frequent in anti-dsDNA + (30.2%), compared with anti-dsDNA ± and anti-dsDNA − (21.1% and 18.7%, resp.;P=0.001). Serositis resulted significantly more frequent in anti-dsDNA − (82.3%) compared to anti-dsDNA + and anti-dsDNA ± (20.8% and 13.4%, resp.;P<0.0001). The reduction of C4 serum levels...
The assessment of disease activity in patients affected by Systemic Lupus Erythematosus (SLE) rep... more The assessment of disease activity in patients affected by Systemic Lupus Erythematosus (SLE) represents an important issue, as recommended by the European League Against Rheumatism (EULAR). Two main types of disease activity measure have been proposed: the global score systems, providing an overall measure of activity, and the individual organ/system assessment scales, assessing disease activity in different organs. All the activity indices included both clinical and laboratory items, related to the disease manifestations. However, there is no gold standard to measure disease activity in patients affected by SLE. In this review, we will analyze the lights and shadows of the disease activity indices, by means of a critical approach. In particular, we will focus on SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), the most frequently used in randomized controlled trials and observational studies. The evaluation of data from the literature underlined some limitations of these indices, making their application in clinical practice difficult and suggesting the possible use of specific tools in the different subset of SLE patients, in order to capture all the disease features.
Objectives. To evaluate the application of Disease Activity Score 28 (DAS28) to assess joint invo... more Objectives. To evaluate the application of Disease Activity Score 28 (DAS28) to assess joint involvement in Systemic Lupus Erythematosus (SLE).Methods. Sixty-nine SLE patients, complaining of joint symptoms, and 44 rheumatoid arthritis (RA) patients were enrolled. In SLE patients disease activity was assessed with SLEDAI-2K. DAS28 was calculated in all the patients.Results. Thirty SLE patients (43.5%) showed clinical signs of arthritis. Mean DAS28 was4.0±1.4, 22 patients (31.9%) had low disease activity, 29 (42.0%) moderate, and 18 (26.1%) high. We dichotomized SLE patients according to the presence (Group 1) or absence (Group 2) of articular involvement according to SLEDAI-2K: 56.3% of the patients of the second group had a moderate/high activity according to DAS28. We compared SLE patients with 44 RA patients (M/F 9/35, mean age55.6±14.5years; mean disease duration140.4±105.6months). No significant differences were found regarding the values of DAS28 between SLE and RA patients. O...
In the present study, we performed a retrospective study on the indication, efficacy and causes o... more In the present study, we performed a retrospective study on the indication, efficacy and causes of withdrawal of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE). Moreover, a review of the literature concerning the use of MMF in the real life was performed. We recorded data about indications, mean dosage, duration of treatment and reasons for drug withdrawal. The efficacy was evaluated according to changes in SLE Disease Activity Index 2000 (SLEDAI-2K), renal SLEDAI-2K and daily proteinuria, after 4 and 12 months of treatment. Six hundred and nine SLE patients were evaluated; among them, 109 patients (17.9 %) were treated with MMF (mean treatment duration 33.9 ± 31.2 months, mean dosage 28.1 ± 10.6 mg/kg). The most frequent indications for using MMF were lupus nephritis (55.9 %) and musculoskeletal manifestations (33.0 %). After 4 and 12 months, a significant reduction of mean SLEDAI-2K, renal SLEDAI and daily proteinuria, compared with baseline, was demonstrated. Thirty-one patients (28.4 %) discontinued MMF therapy (mean treatment duration at the time of discontinuation 17.5 ± 21.2 months). The incidence risks of MMF discontinuation due to inefficacy and side effects were 0.09 and 0.1, respectively. Patients with disease duration longer than 36 months (70.6 %) had a significant increased risk of MMF withdrawal (RR 0.4, P = 0.03). The results of the present study demonstrated that MMF should be considered a treatment option for SLE manifestation other than renal involvement in daily clinical practice.
Uploads
Papers by Laura Massaro