G. Canestrari

Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset still's disease: A multicentre retrospective observational study

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still’s disease (AOSD). Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot’s score was used to evaluate disease severity. Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot’s score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot’s score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

Prognostic Role of Ventricular Ectopic Beats in Systemic Sclerosis: A Prospective Cohort Study Shows ECG Indexes Predicting the Worse Outcome

Background Arrhythmias are frequent in Systemic Sclerosis (SSc) and portend a bad prognosis, accounting alone for 6% of total deaths. Many of these patients die suddenly, thus prevention and intensified risk-stratification represent unmet medical needs. The major goal of this study was the definition of ECG indexes of poor prognosis. Methods We performed a prospective cohort study to define the role of 24h-ECG-Holter as an additional risk-stratification technique in the identification of SSc-patients at high risk of life-threatening arrhythmias and sudden cardiac death (SCD). One-hundred SSc-patients with symptoms and/or signs suggestive of cardiac involvement underwent 24h-ECG-Holter. The primary end-point was a composite of SCD or need for implantable cardioverter defibrillator (ICD). Results Fifty-six patients (56%) had 24h-ECG-Holter abnormalities and 24(24%) presented frequent ventricular ectopic beats (VEBs). The number of VEBs correlated with high-sensitive cardiac troponin T (hs-cTnT) levels and inversely correlated with left-ventricular ejection fraction (LV-EF) on echocardiography. During a mean follow-up of 23.1±16.0 months, 5 patients died suddenly and two required ICD-implantation. The 7 patients who met the composite end-point had a higher number of VEBs, higher levels of hs-cTnT and NT-proBNP and lower LV-EF (p = 0.001 for all correlations). All these 7 patients had frequent VEBs, while LV-EF was not reduced in all and its range was wide. At ROC curve, VEBs>1190/24h showed 100% of sensitivity and 83% of specificity to predict the primary end-point (AUROC = 0.92,p<0.0001). Patients with VEBS>1190/24h had lower LV-EF and higher hs-cTnT levels and, at multivariate analysis, the presence of increased hs-cTnT and of right bundle branch block on ECG emerged as independent predictors of VEBs>1190/24h. None of demographic or disease-related characteristics emerged as predictors of poor outcome. Conclusions VEBS>1190/24h identify patients at high risk of life-threatening arrhythmic complications. Thus, 24h-ECG-Holter should be considered a useful additional risk-stratification test to select SSc-patients at high-risk of SCD, in whom an ICD-implantation could represent a potential life-saving intervention.

QTc interval prolongation in Systemic Sclerosis: Correlations with clinical variables and arrhythmic risk

Article history: Received 13 March 2017 Accepted 16 March 2017 rhythmias, irrespective of QTc interval duration, as well as the potential life-saving role of an ICD-based approach in SSc patientswith cardiac involvement and a high number of VEBs on 24h ECG-Holter [3–5]. On that basis, the authors pathogenetic speculations should be taken with caution before extrapolating them to clinical practice considering the un-

Tumour-associated antigens in systemic sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk

OBJECTIVE To evaluate the serum levels of tumour-associated antigens (TAAs) in patients with SSc and interstitial lung disease (ILD) and to define whether their levels mirror the severity and the progression of lung damage. METHODS Data from 80 SSc patients with ILD were collected at baseline and after 2 years as well as from 40 SSc controls without ILD. The occurrence of any malignancy was recorded. RESULTS At baseline, an increase of at least one TAA was present in 35 SSc patients with ILD compared with 6 SSc patients without ILD (P < 0.0001); this was associated with lower forced vital capacity (FVC) and higher interstitial and alveolar scores. Levels of carbohydrate antigen 15-3 and carcinoembryonic antigen inversely correlated with FVC and directly correlated with alveolar and interstitial scores and their levels were higher in patients who presented a progression of lung damage after 2 years. During 4 years of follow-up, a malignancy was detected in seven patients who already had an increase of at least one TAA. Values of TAAs increased over time in patients who developed cancer, while their trend remained stable in the others. At multivariate analysis, to have three or more TAAs emerged as a strong independent predictor of the development of malignancies [relative risk 24.1 (95% CI 1.8, 315.0), P = 0.02]. CONCLUSION TAAs can be elevated in the sera of SSc patients and correlate with the degree of lung damage, suggesting a role as severity biomarkers. Close follow-up is necessary in SSc patients because of the increased cancer risk overall in patients with increased TAAs.

Free light chains of immunoglobulins in patients with systemic sclerosis: correlations with lung involvement and inflammatory milieu

Aim Humoral immunity and B cells are thought to play an important role in the pathophysiology of the systemic sclerosis (SSc). The production of free light chains (FLC) of immunoglobulins is abnormally high in several pathological autoimmune conditions and reflects B cell activation. Furthermore, FLCs demonstrated different biological activities including their capability to modulate the immune system, proteolytic activity and complement cascade activation. The aims of this study are to determine the FLC levels in patients with SSc compared with healthy controls (HC) and to study their possible association with organ involvement and disease characteristics. Methods Sixty-five patients with SSc and 20 HC were studied. Clinical and immunological inflammatory characteristics were assessed for all the patients with SSc. κ-FLC and λ-FLC, interleukin 6 (IL-6) and B cell activating factor levels were measured. Results The mean serum κ-FLC levels and FLC ratio were significantly higher in patients with SSc compared with HC, while the serum λ-FLC levels were comparable. The levels of FLC were comparable in patients with diffuse skin disease and limited skin involvement, while κ-FLC levels were increased in patients with restrictive lung (forced vital capacity (FVC) <80%) disease (26.4±7.4 mg/L) when compared with patients with FVC ≥80% (19.6±7.3 mg/L, P=0.009). In patients with SSc, the levels of serum κ-FLC level directly correlated with the IL-6 levels (R=0.3, P=0.001) and disease activity (R=0.4, P=0.003). Conclusions FLC levels are elevated in SSc and high levels are associated with lung involvement and with a higher degree of inflammation, supporting a possible role of B cell activation in the pathophysiology of the disease.

Cardiac troponin T and NT-proBNP as diagnostic and prognostic biomarkers of primary cardiac involvement and disease severity in systemic sclerosis: A prospective study

OBJECTIVES The aim of our study was to define the role of high-sensitive cardiac troponin T (hs-cTnT) and NT-proBNP in identifying Systemic Sclerosis (SSc) patients with cardiac involvement and at higher risk of cardiac death. METHODS Plasma hs-cTnT and NT-proBNP concentrations were measured in 245 SSc-patients. RESULTS hs-cTnT and NT-proBNP levels were higher in SSc-patients than in healthy controls. Hs-cTnT levels were higher than 0.014 ng/ml in 32.3% SSc-patients, while NT-proBNP was above 125 pg/ml in 31.8% of them, irrespective of classical cardiovascular risk factor and of pulmonary arterial hypertension. Elevated hs-cTnT and NT-proBNP were associated with diffuse skin involvement and directly correlated with the skin score. Patients with increased cardiac markers presented a lower left-ventricular ejection fraction (LVEF) and a higher rate of right bundle branch block (RBBB) on electrocardiogram (ECG) compared to patients with normal cardiac enzymes. During the follow-up, 12 SSc-patients experience a disease-related death; 9 of these were directly related to cardiac involvement (sudden cardiac death or heart failure) and the majority of them occurred among patients with increase of at least one cardiac biomarker. Long-term survival was worse in patients with increase of both cardiac biomarkers. CONCLUSIONS Evaluation of hs-cTnT and NT-proBNP levels may provide a tool to screen non-invasively SSc-patients for heart involvement. A higher incidence of impaired systolic function, ECG abnormalities and a poor outcome in SSc-patients with elevated cardiac enzymes suggests that they may be valuable screening biomarkers to detect a cardiac damage at early stages and to improve risk stratification.

OP0107 Adipocytokines imbalance is associated with vascular damage in systemic sclerosis

Background Adipocytokines are implicated in the development of fibrosis, vasculopathy and immune abnormalities through a variety of biological effects, but their role in systemic sclerosis (SSc) is not fully investigated. Chemerin is implicated in chemotaxis of immune cells, in promoting angiogenesis and it is involved in inflammation. Adiponectin (APN) has metabolic actions and anti-inflammatory properties, while Leptin (LEP) mediates actions in endothelial cells, such as angiogenesis, vasodilation, NO production and upregulates various mediators of vascular inflammation. Objectives In this study we investigated Chemerin, LEP and APN levels in SSc patients according to disease subtypes and clinical characteristics. Methods Chemerin, LEP and APN levels were evaluated in 100 SSc patients and in sex, age and BMI matched healthy controls. Clinical and demographical characteristics were available for all patients. Results Chemerin, APN and LEP levels were lower in SSc patients compared to healthy controls (Chemerin: 58.7±27.6 ng/ml vs 74.0±29.0 ng/ml, p=0.004; LEP:19.6±18.3 ng/ml vs 28.5±23.8 ng/ml, p=0.03, APN: 6.5±3.9 µg/ml vs 12.8±6.0 µg/ml, p<0.001) Chemerin levels were lower in patients with anti-topoisomerase antibodies (50.2±22.7 ng/ml) respect to patients with other autoantibodies (64.6±29.7 ng/ml), p=0.018. Regarding capillaroscopic damage, Chemerin levels were lower in patients with late pattern (44.8±18.9 ng/ml) compared to patients with early (64.3±28.5 ng/ml) and active pattern (71.7±29.9 ng/ml), p<0.001. APN levels inversely correlate with IL-6 levels (R=-0.4, p<0.001), while directly correlate with capillary density (R=0.3,p=0.03). Patients with avascular areas presented lower levels of APN (5.3±3.9 µg/ml) compared to patients without avascular areas (7.3±3.4 µg/ml),p=0.005. LEP levels directly correlate with vascular density on nailfold capillaroscopy (R=0.3, p=0.02), confirming the role of LEP in endothelial homeostasis. Furthermore, patients with avascular areas presented lower LEP levels (15.5±13.0 ng/ml) compared to patients without avascular areas (31.1±28.4 ng/ml), p=0.003. LEP levels were lower in patients with active digital ulcers (9.3±6.6 ng/ml), compared to patients without ulcers (9.3±6.6 ng/ml), p=0.01. The anti-inflammatory and endothelium protective role of APN emerged also when we considered the lung involvement: in fact patients with DLCO >50% presented higher levels of APN (7.0±3.9 µg/ml) compared to patients with DLCO <50% (5.8±3.8 µg/ml), p=0.05. Considering the cardiopulmonary involvement, LEP levels inversely correlate with PAPs on echocardiography (R=-0.24, p=0.02). Finally LEP levels inversely correlate with skin score (R=-0.3, p=0.009) and patients with early disease presented lower LEP levels (15.1±13.2 ng/ml) compared to patients with long lasting disease (29.9±28.7 ng/ml), p=0.006. Conclusions Our data suggest an imbalance of the levels of adipocytokines in SSc, their down-regulation in patients with a more aggressive pattern on nailfold videocapillaroscopy and organ damage, suggesting a possible role of Chemerin, LEP and APN in the impaired angiogenesis and in the development of vasculopathy of SSc patients. Disclosure of Interest None declared

FRI0238 Increased Serum Free Light Chains of Immunoglobulins in Systemic Sclerosis Patients: Correlation with Lung Involvement and Inflammatory Milieu

Background Humoral immunity and B cells are thought to play an important role in the pathophysiology of the systemic sclerosis (SSc). The production of free light chains (FLC) of immunoglobulins is abnormally high in different pathological autoimmune conditions and reflects B cell activation. Furthermore FLCs demonstrated different biological activities including their capability to modulate the immune system, proteolytic activity, complement cascade activation, as well as FLC binding to antigens and chemotactic factors. Objectives To determine the FLC levels in patients with SSc and in healthy controls and to study their possible association with organ involvement and disease characteristics. Methods Sixty-five SSc patients (90.0% females; mean age 50.8±17.0 years; 27 (41.5%) with diffuse skin involvement-dcSSc) and 20 age and sex matched healthy controls (HC) were studied. Clinical and immunological inflammatory characteristics were assessed for all the SSc patients. FLC levels were quantified by nephelometry (Freelite TM Human Kappa and Lambda Free Kits, The Binding Site, UK). IL6 and BAFF levels were measured in SSc patients by ELISA. Results The mean serum FLC-κ level (SSc: 20.4±7.5 ng/ml vs HC 9.4±4.3 ng/ml, p<0.001) and FLC ratio (SSc: 1.6±0.6 vs HC 0.8±0.2, p<0.001) were significantly higher in patients with SSc compared to healthy controls, while the serum FLC-λ levels were comparable (SSc: 13.6±4.8 ng/ml vs HC 11.9±6.2 ng/ml, p=ns). The levels of FLC were comparable in patients with diffuse skin disease and limited skin involvement, while FLC-κ levels were increased in patients with restrctive lung (FVC<79%) disease (SSc: 26.4±7.4 ng/ml) when compared to patients with FVC>79% (HC 19.6±7.3 ng/ml, p=0.009). In SSc patients the levels of serum FLC-κ level directly correlate with the IL-6 levels (R=0.6, p<0.001), while no correlation was found with skin involvement and autoantibodies distribution. Conclusions Free light chains of immunoglobulins (sFLC) levels are elevated in systemic sclerosis. High levels of sFLC are associated with the fibrotic lung involvement and with an higher degree of inflammation, supporting the role of B cell activation in the pathophysiology of SSc. Disclosure of Interest None declared

AB0699 Beta-Blockers Control Frequent Ventricular Ectopic Beats in Systemic Sclerosis: A Monocentric Study

Background Ventricular ectopic beats (VEBs) are associated with a substantial increase in the risk of sudden and total cardiac death, both in the general population and in Systemic Sclerosis (SSc) patients (1,2). Beta-blockers are the mainstay of medical suppression of VEBs but are not routinely used in SSc patients due to possible Raynauds phenomenon exacerbation and digital ischemic complications. Objectives To evaluate safety and effectiveness of beta-blockers in SSc patients with heart involvement and arrhythmic burden. Methods 96 patients of our cohort with signs and/or symptoms suggestive of cardiac involvement (dyspnoea, palpitations and/or rise of cardiac enzymes) underwent 24h-ECG-Holter. Among these, 14 patients with palpitations and/or frequent VEBs were treated with beta-blockers and prospectively followed. Ten patients were treated with bisoprolol (doses between 1.25-5 mg/day) and 4 with carvedilol. A complete assessment of disease characteristics and cardiac involvement was also performed and, after a mean follow-up of 14.0±9.4 months, a second 24h-ECG-Holter was performed. The effects on active ulcers were examined. Results Eighteen patients (18.9%) presented VEBs >1000/24h at baseline. Considering the 14 patients treated with beta-blockers (mean age:47.5 years; mean disease duration:6.4 years; diffuse disease:57.1%; anti-Scl70 positivity: 64.3%), all of them presented an increase of troponin T and 8 (57.1%) a right bundle branch block. An history of digital ulcers was present in the majority of patients (71.4%) and 7 of them (50%) presented active ulcers at the time of study enrolment, 3 of whom with tissue loss. All patients were on sinus rhythm and none of them presented ST/T alterations; the mean number of VEBs at baseline was strikingly higher (6917.4±9911.9/24h) and 9 patients (64.3%) had a number of VEBs>1000/24h, that were polymorphic in 6 (42.8%). In 6 patients (42.8%), moreover, an episode of non-sustained ventricular tachycardia (NS-VT), the longest of 34 beats, was recorded. After beta-blockers treatment, the number of VEBs decreased in 10 patients (71.4%). The relative mean reduction was 74.7% (range:41.7-100%), while the absolute mean reduction was 4753.4±5610 VEBs/24h, with a range of 183-14408 VEBs/24h. The number of VEBs remained stable in the only 3 patients who presented a baseline number of VEBs<30/24h, and it increased in one patient. Considering the 9 patients with VEBs>1000/24h at baseline, in 3 (33.3%) the treatment with bisoprol led the number of VEBs far below this prognostic cut-off value, while among the 6 patients with baseline NS-VT, 3 had no more episodes recorded at follow-up. Despite continuative beta-blocker therapy, none of the patients presented a worsening of digital and legs ulcers, that rather improved in 4 patients, and none developed new digital ulcers. The Raynauds phenomenon remained stable in all patients. Conclusions Despite the small number of patients in this pilot study, our data suggest the efficacy of beta-blockers in reducing VEBs without an increase of digital ulcers complication or worsensing of Raynauds phenomenon. References Kostis JB. Am J Med 1988;84:1007-14. Ataklte F. Am J Cardiol 2013;112:1263-70. Disclosure of Interest None declared

FRI0487 Cardiac Magnetic Resonance in the Evaluation of Symptomatic Patients with Systemic Sclerosis: Correlation with Clinical Characteristics and Arrhythmic Burden

Background Cardiovascular magnetic resonance imaging (CMRI) has been proposed as a useful tool for early assessment of sub-clinical cardiac involvement in Systemic Sclerosis (SSc). Objectives To evaluate the role of CMRI in the detection of cardiac involvement in selected SSc patients. Methods Fifty SSc-patients with symptoms of cardiac involvement (dyspnea, palpitations) and/or elevation of cardiac troponin T underwent CMRI. Twenty sex and aged matched healthy controls were also enrolled. Clinical and cardiac (echocardiography and 24h-ECG-Holter) characteristics were available for all scleroderma patients. Results SSc patients and healthy controls presented comparable end-diastolic volume (EDV) and end-systolic volume (ESV) of right and left ventricles. Despite SSc patients presented lower left ventricle ejection fraction (EF)(61.2±10.8%) and lower right ventricle EF (57.5±12.2%) compared to healthy controls (LVEF:64.3±4.9% and RVEF:61.2±3.6%), the differences were not statistically significant. Nineteen SSc patients (38%) presented abnormalities on CMRI study, with respect to none of the healthy controls. CMRI demonstrated T2 hyperintensity in 5 SSc patients (10%), while none of the patients presented early gadolinium enhancement and 17 (34%) patients presented late gadolinium enhancement (LGE). We identified 3 different patterns of distribution of LGE: subepicardial, midwall and subendocardial. Fourteen patients (82.3%) presented a single pattern of distribution, while 3 patients (17.7%) presented more than one: 58.8% of patients presented a midwall distribution of LGE, 29.4% of patients presented a subepicardial LGE with a linear distribution pattern and 35.3% presented a subendocardial LGE distribution. Twelve SSc patients (38%) showed hypokinetic area and only one patient an akinetic area. Twenty-two SSc patients (44.0%) presented a pericardial effusion on CMRI. Patients with CMRI abnormalities presented a longer disease duration (10.1±5.6 years) when compared with SSc patients without CMRI abnormalities (4.3±7.6 years, p=0.003). Furthermore, LVEF and RVEF were lower in patients with CMRI abnormalities, while ESV of both ventricles was higher in these SSc patients when compared to SSc patients with normal CMRI. Finally, in SSc patients LVEF inversely correlated with disease duration (R=-0.3, p=0.035) and number of ventricular ectopic beats (VEBs) on 24h-ECG Holter (R=-0.3, p=0.04). Interestingly, considering the right ventricle, the number of VEBs inversely correlated also with EF (R=-0.4, p=0.04) and directly correlated with EDV (R=0.4, p=0.01) and ESV (R=0.5, p=0.002). Conclusions CMRI could be a useful tool to detect abnormal ventricular function and volumes and allows to identify cardiac abnormalities (T2 hyperintensity and LGE) in a subgroup of scleroderma patients. Even though the correlations between EF, end-systolic and diastolic volumes of both ventricles and some clinical characteristics (disease duration and number of VEBs) suggest a possible clinical significance of CMRI abnormalities, their real clinical value need to be further investigated. Disclosure of Interest None declared