C. Stagnaro

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0–2.0 mg/kg/day) among adults and 2–4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.

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.

Epidemiology and Management of Neuropsychiatric Disorders in Behçet’s Syndrome

Behçet’s syndrome (BS) is a systemic, chronic, relapsing vasculitis, typically characterized by recurrent orogenital ulcers, ocular inflammation and skin manifestations; articular, vascular, gastroenteric and neurological involvement may also occur. Besides the other clinical features of BS, it seems relatively frequent that patients with BS develop a neurobehavioural syndrome, characterized by euphoria, bipolar disorders and paranoid attitudes, loss of insight/disinhibition, and indifference to their disease, defined as ‘neuro-psycho-BS’. To date, the pathogenetic mechanism underlying neuro-psycho-BS has not been determined. It may be secondary to organic neurological involvement, or it may be related to poor quality of life and the relapsing course of the disease. Another engaging theory suggests that it could be related to the frequent observation of psychiatric symptoms during relapses or, in some cases, in the phases preceding reactivation of the disease; these elements suggest that psychiatric disorders in BS could represent a crucial element, whether a psychiatric subset or a distinct clinical feature of the disease. Moreover, it has been reported that cognitive impairment in BS can be seen with or without central nervous system involvement. Globally, psychiatric symptoms have been described as being multifaceted, ranging from anxiety disorders to depressive–bipolar disorders or to psychotic ones. In addition, some psychological characteristics of BS patients seem to predispose them to maladaptive stress management, which may lead to stress-related disorders, including anxiety and depression. Therefore, the aims of this review are to explore the epidemiology of neuro-psycho-BS by evaluating the relationship between the stress system and the multifaceted psychiatric manifestations in BS, and to summarize the therapeutic strategy used.

High sensitivity troponin might be a marker of subclinical scleroderma heart involvement: a preliminary study

Introduction Although often asymptomatic, cardiac involvement is common in systemic sclerosis (SSc), and is associated with an increased morbidity and mortality. The aim of this study is to investigate whether high-sensitivity troponin (HSTn) might represent a useful tool to detect subclinical scleroderma heart involvement (SHI) in SSc. Methods We enrolled 65 consecutive SSc patients who performed HSTn test, electrocardiogram and an echocardiogram within six months of HSTn test. We acquired also data about N-terminal segment of proBNP (NT-proBNP) and cardiac magnetic resonance imaging (cMRI). We excluded patients with overt pulmonary arterial hypertension. We defined as subclinical SHI the presence of the following conditions: diastolic dysfunction, pericardial effusion, conduction abnormalities/arrhythmias, oedema and/or T2 weighted non-ischemic pattern showed by cMRI. Results Twelve patients showed SHI, and 23 and 29, respectively, had high levels of HSTn and of NT-proBNP. SHI is correlated with high levels of HSTn (p = 0.02) with a significant difference between HSTn values in patients with or without SHI (59 vs. 13 ng/mL; p = 0.0097). Moreover, among patients with abnormal NT-proBNP, 18 also had out of range HSTn (Spearman rank correlation 0.5; p<0.0001). According to ROC curve analysis, the best HSTn cut-off value in distinguishing between patients with and patients without SHI was 16 ng/mL (sensitivity 66.7%, specificity 83%; area under the curve: 0.77 (95% CI: 0.65-0.87) p<0.001. Conclusions Our data show a close relationship between HSTn and NT-proBNP in SSc patients with SHI. HSTn might be a marker of SHI while NT-proBNP seems to be less specific for heart dysfunction.

Post-occlusive reactive hyperaemia (POHR) in systemic sclerosis: very early disease (VEDOSS) represents a separate entity compared to established disease

Objectives: Vascular involvement is a key feature of systemic sclerosis (SSc). Vascular changes are central to the pathogenesis of the disease and the assessment of vascular involvement has a prognostic value. This assessment therefore has a pivotal role in the management of SSc patients. The aim of our study was to evaluate post-occlusive reactive hyperaemia (PORH) in consecutive SSc patients and to test whether a PORH test might be a useful tool for the early diagnosis of SSc. Method: Between April 2011 and April 2015, 60 consecutive SSc patients (mean age 56 ± 15 years, females:males = 18:1) were enrolled in the study. The patients were divided into those with full-blown SSc (n = 50) and those with very early diagnosis of SSc (VEDOSS) (n = 10) according to the literature. Laser speckle contrast analysis (LASCA) was used to assess PORH. Results: A statistically significant difference was detected in the post-ischaemic hyperaemic peak flow between VEDOSS and established SSc (424% vs. 137%, p = 0.0011). PORH peak flow decreased according to the capillaroscopic pattern (early = 419%, active = 163%, late = 145%, p = 0.0027). Moreover, a correlation between capillary density and peak flow was revealed (rho = 0.33, p < 0.01). Conclusions: These data show a different pattern of vascular involvement in VEDOSS compared to established disease that mirrors capillaroscopic changes. Functional features of very early and established disease seem to be the physiological counterpart of abnormalities detected by capillaroscopy. The POHR test might be a useful aid for further characterization of vascular involvement in SSc. In particular, blunted POHR might prove a tool to separate pre-clinical from full-blown SSc.

Remission and low disease activity in systemic lupus erythematosus: an achievable goal even with fewer steroids? Real-life data from a monocentric cohort

Objectives To evaluate what proportion of patients fulfil the DORIS definition of remission, the definition of lupus low disease activity state (LLDAS) and LLDAS with a glucocorticoid (GC) dosage ≤5 (LLDAS5) in a longitudinal monocentric cohort of patients with SLE; to identify predictors of sustained remission and LLDAS attainment; to evaluate the effect of sustained remission and LLDAS on damage accrual over a period of 5 years and compare the two conditions in terms of clinical outcomes. Methods Retrospective analysis of data prospectively collected from patients with SLE followed from 2012 to 2016. Results 115 patients were included in this analysis. At baseline, 72% of patients were on LLDAS and almost all patients also fulfilled the LLDAS5 definition; 45% of patients were in remission on treatment, 12% were in remission off treatment, 26% were in complete remission on treatment, 2% were in complete remission off treatment. Disease activity at baseline was the strongest predictor of subsequent LLDAS and remission; the presence of joint and cutaneous manifestations was associated with a minor likelihood to achieve LLDAS or remission during follow-up. Patients in remission and LLDAS for the whole follow-up period accrued significantly less organ damage; on the contrary, patients who maintained all kinds of remissions or LLDAS for less than 50% of the time did not show any differences in damage accrual with respect to the rest of the cohort. Conclusion Remission and LLDAS, even with reduced GC use, are an achievable goal in clinical practice; sustained LLDAS and remission are both associated with reduced damage accrual.

PS8:161 The disease burden in patients with longstanding systemic lupus erythematosus: focus on health resource use and costs

Introduction As a consequence of increased SLE patients survival, patients with long disease duration represent a significant proportion of our cohorts. This study aims to evaluate health resource use and the 6 months costs in patients with SLE with long disease duration. Methods The economic evaluation was performed in terms of cost-of-illness analysis as part of a larger study enrolling SLE patients with at least 15 years of disease duration regularly followed at our unit. At enrollment, the following information were collected: disease activity (SLEDAI), organ damage (SLICC-DI score), comorbidities, treatment patterns; in addition to clinical data, patients were required to complete an ad-hoc questionnaire for the collection of facts relevant for the estimation of the economic dimension and covering the previous six-months. Such a time frame was considered to be appropriate as recall period. Direct health (drugs, hospitalizations, emergency visits, specialists visits, laboratory tests and instrumental examination) and non-health costs (transportation and accommodation) as well as indirect costs because of productivity loss were estimated. Results 51 adult patients with long disease duration were recruited (98% female, mean age 49±11 years, median disease duration 17 years, IQR 15–23). Median (IQR) SLEDAI score was 2 (0–4), median SLICC-DI was 1 (0–2). The median (IQR) direct health costs per patients over the previous 6 months resulted 410€ (201–1687); indirect costs because of productivity lost were 130€ (0–356). The median overall cost to the Society was 473€ (327–2148); the presence of comorbid conditions resulted associated with higher overall cost for the Society (552€ [327–1807] vs 264€ [94–1164] p=0.046); disease activity and damage at enrollment were not associated with costs increase in this cohort. Conclusions This cohort of patients with long lasting disease is characterised by low disease activity and mild organ damage; in this setting, the disease burden on the single patient and family is significant and the costs to the Society are influenced by the presence of comorbidities.Abstract PS8:161 Table 1

Translation, cultural adaptation and validation of the Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) in a cohort of Italian systemic lupus erythematosus patients

Introduction The Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) is a patient-reported instrument for the assessment of disease activity in systemic lupus erythematosus (SLE). The aims of the present study are translation, cultural adaptation and validation of an Italian version: the SLAQit. Methods The process of translation and cultural adaptation followed published guidelines. SLAQit was pretested in a group of 35 SLE patients to evaluate acceptability, comprehension and feasibility. Internal consistency, test–retest validity and external validity were tested on consecutive SLE patients attending the clinic. Results In total, 135 SLE patients were enrolled in this study. The pilot test provided a 99.9% response rate and demonstrated feasibility and comprehensibility of the questionnaire. A good internal consistency was found among the three components of the score (SLAQ score, numerical rating scale (NRS), patient global assessment question (PGA); α = 0.79). SLAQit showed very high reliability (test–retest α > 0.8). NRS and PGA showed a strong positive correlation with both Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (p = 0.002 and p < 0.001, respectively) and European Consensus Lupus Measurement (ECLAM) scores (p = 0.01 and p < 0.001, respectively), while the SLAQ score did not. A significant agreement was observed between the physicians intention to treat and both the NRS and PGA scores, while no significant association was reported with the SLAQ score. Conclusions SLAQit was demonstrated to be a reliable and valid instrument for self-assessment of disease activity in SLE patients.

FRI0344 Novel biomarkers of subclinical endothelial dysfunction in behÇet's syndrome: evaluation of cross-sectional distensibility and intima-media-thickness in a hospital-based population

Background Growing interest exists on the role of markers of subclinical cardiovascular disease as independent predictors of cardiovascular events. Poor data are available on the role of these markers as prognostic factors for Behçets syndrome (BS). Objectives The primary aim was to explore Intima-Media-Thickness (IMT), mean arterial diameter and distensibility (DC) in a group of patients with BS, comparing these data with a healthy control group and a disease control group; the secondary aim was to correlate the vascular parameters with demographic/clinical profile. Methods Thirty BS patients (females:12;mean age±SD:43±10.5; mean disease duration±SD:13±5.8) fulfilling the ISG criteria were prospective enrolled. Demographic data, level of disease activity, frequency of smokers, hypertension, family history of cardiovascular risk factors, body mass index (BMI) and current therapies were analysed. For each subject, ultrasound B-mode image sequences of right common carotid arteries were acquired and analysed by an automatic system (Carotid Studio,Quipu) for the measurement of IMT and mean arterial diameter. In addition, carotid pulse pressure (PP) was estimated by tonometry and DC coefficient was obtained. The systolic and diastolic carotid diameters were automatically measured on the distal wall of the common carotid artery, 1–2 cm beneath the bifurcation. Carotid diameter was calculated as the distance between media-adventitia interfaces. Cross-sectional DC was estimated through the variations in arterial cross-sectional area and blood pressure during systole. DC was computed as DC=ΔA/(PP*A) where A is the diastolic lumen area, ΔA is the stroke change in lumen area, and PP is the local pulse pressure. Results At time of evaluation, 4/17 patients presented active disease (50% ocular involvement, 25% joint involvement, 25% gastro-enteric involvement; mean BS activity score 5). Mean IMT±SD value resulted of 0.57±0.81, mean arterial diameter±SD value was 6.879±0.81 and mean DC± SD 27.3±14.34. All the vascular parameters considered were significant correlated with BMI, while only IMT and DC were also significant correlated with arterial hypertension. Using a correction analysis for age and sex, we found significant correlations between mean arterial diameter and disease activity and between DC and disease duration. These data resulted significantly different compared to healthy control and a disease control groups, in terms of smaller arterial diameter and higher DC. Conclusions Our data have shown that there is a consistent influence of disease activity and duration of disease on mean arterial diameter and DC, respectively. Thus, it is desirable that future pharmacological researches on BS target on this issue. Acknowledgements Seyahi E, Ugurlu S, Cumali R, Balci H, Ozdemir O, Melikoglu M, Hatemi G, Fresko I, Hamuryudan V, Yurdakul S, Yazici H. Atherosclerosis in Behçets Syndrome. Semin Arthritis Rheum. 2008 Aug;38(1):1–12. Seyahi E, Ugurlu S, Cumali R, Balci H, Ozdemir O, Melikoglu M, Hatemi G,Fresko I, Hamuryudan V, Yurdakul S, Yazici H. Atherosclerosis in BehçetsSyndrome. Semin Arthritis Rheum. 2008 Aug;38(1):1–12. Disclosure of Interest None declared

Hepatitis C and Mixed Cryoglobulinemia: An Update

Cryoglobulinemic vasculitis (CV) or cryoglobulinemic syndrome is a chronic small vessel vasculitis characterized by serum positive cryoglobulins, namely immune complexes which precipitate or form a gel at a temperature less than 37°C and redissolve after rewarming. Mixed cryoglobulinemia, is triggered by chronic hepatitis C virus (HCV), but it may also, less commonly, complicate connective tissue diseases, lymphoproliferative disorders and other chronic infections. In the last decades a number of steps forward have been made in the knowledge of this disorder and CV has changed from being considered solely an immune-complex mediated disease to a viral triggered condition. Nowadays we view this disease as a multifaceted condition with autoimmune features, triggered by HCV infection, coexisting with chronic smouldering lymphoproliferative process which usually remains unmodified for years or even decades, but which can turn into a frank malignant lymphoma on long-term follow-up in a limited numbers of cases. In this chapter we will review most recent progresses in this disease.Abstract Cryoglobulinemic vasculitis (CV) or cryoglobulinemic syndrome is a chronic small vessel vasculitis characterized by serum positive cryoglobulins, namely immune complexes which precipitate or form a gel at a temperature less than 37°C and redissolve after rewarming. Mixed cryoglobulinemia, is triggered by chronic hepatitis C virus (HCV), but it may also, less commonly, complicate connective tissue diseases, lymphoproliferative disorders and other chronic infections. In the last decades a number of steps forward have been made in the knowledge of this disorder and CV has changed from being considered solely an immune-complex mediated disease to a viral triggered condition. Nowadays we view this disease as a multifaceted condition with autoimmune features, triggered by HCV infection, coexisting with chronic smouldering lymphoproliferative process which usually remains unmodified for years or even decades, but which can turn into a frank malignant lymphoma on long-term follow-up in a limited numbers of cases. In this chapter we will review most recent progresses in this disease.