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Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV.

Leukocytoclastic vasculitis (LCV) is a histopathologic description of a common form of small vessel vasculitis (SVV), that can be found in various types of vasculitis affecting the skin and internal organs. The leading clinical presentation of LCV is palpable purpura and the diagnosis relies on histopathological examination, in which the inflammatory infiltrate is composed of neutrophils with fibrinoid necrosis and disintegration of nuclei into fragments (“leukocytoclasia”). Several medications can cause LCV, as well as infections, or malignancy. Among systemic diseases, the most frequently associated with LCV are ANCA-associated vasculitides, connective tissue diseases, cryoglobulinemic vasculitis, IgA vasculitis (formerly known as Henoch–Schonlein purpura) and hypocomplementemic urticarial vasculitis (HUV). When LCV is suspected, an extensive workout is usually necessary to determine whether the process is skin-limited, or expression of a systemic vasculitis or disease. A comprehensive history and detailed physical examination must be performed; platelet count, renal function and urinalysis, serological tests for hepatitis B and C viruses, autoantibodies (anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies), complement fractions and IgA staining in biopsy specimens are part of the usual workout of LCV. The treatment is mainly focused on symptom management, based on rest (avoiding standing or walking), low dose corticosteroids, colchicine or different unproven therapies, if skin-limited. When a medication is the cause, the prognosis is favorable and the discontinuation of the culprit drug is usually resolutive. Conversely, when a systemic vasculitis is the cause of LCV, higher doses of corticosteroids or immunosuppressive agents are required, according to the severity of organ involvement and the underlying associated disease.

Background The aim of this study was to evaluate and compare the internal and external responsiveness of a computed-aided method (CaM) with a conventional visual reader-based score (CoVR) to measure interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) on high resolution computed tomography (HRCT). Methods Forty-five patients were evaluated in this retrospective cohort. HRCTs were collected at baseline and after 1 year. HRCT abnormalities were evaluated according to a CoVR (Warrick's method) and a quantitative CaM. Internal 1-year responsiveness was tested with a standardized mean response (SRM). Analyses of the receiver operating characteristic curves (ROCs) evaluated the sensitivity and specificity of the two methods to discriminate between clinically relevant progression and no relevant progression, using expert judgment as the gold standard (external responsiveness). Results In one year, lung involvement was stable/improved in 17 of the 45 patients (37.8%) and worsened in 28 patients (62.2%). HRCT scores changed moderately over the follow-up period. Using SFM, CaM was significantly more responsive in detecting changes due to treatment than the CoVR method. Likewise, in the analysis of the ROC curve, CaM scores showed the highest performance (AUC ROC CaM vs. CoVR, 0.951 vs. 0.807; p = 0.0065). Conclusion Quantitative analysis of CaM was more responsive than the CoVR method to accurately evaluate and monitor SSc-ILD progression or response to therapy.

Summary Background Systemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. Methods Evidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. Findings Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. Interpretation Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. Funding An unrestricted grant from Boehringer Ingelheim International.

Mixed cryoglobulinaemic vasculitis (MCV) is an immune-complex-mediated systemic vasculitis characterised by heterogeneous clinical manifestations mainly involving lymphatic system, skin, kidney and peripheral nervous system. Although MCV patients have been included in priority programs for vaccination against SARS-CoV-2 in Italy, limited information is available for these patients. Aims of this multicentre Italian study were to investigate SARS-CoV-2 vaccination rate in MCV patients and its safety profile.All MCV patients referring to participating centres were assessed with an interview-based survey about vaccination, reasons for not getting vaccinated, adverse events (AE), and disease flares within a month after vaccination.A total of 416 patients were included in the study. Among participants, 7.7% did not get vaccinated, mainly for fear related to vaccine side-effects (50%) or medical decision (18.8%). They were more frequently treated with chronic glucocorticoids or rituximab (p=0.049 and p=0.043, respectively). Mild and self-limiting AE were recorded in 31.7% of cases, while post-vaccination vasculitis flares were observed in 5.3% of subjects. Disease relapses were mainly observed in patients with peripheral neuropathy or skin vasculitis (40% and 25%, respectively).Vaccination against SARS-CoV-2 has been performed in a high percentage of MCV patients with encouraging safety profile. Vasculitis flares rate was in line with that observed for other autoimmune diseases, despite patients with purpura or peripheral neuropathy seem to be at risk for symptoms' exacerbation. Patients' hesitancy, rituximab and glucocorticoids treatment were the main reasons for delaying vaccination.

OBJECTIVE Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Environmental agents and occupational exposures may confer susceptibility to EGPA, but data are scarce. This study was undertaken to investigate the association between occupational exposures (e.g., silica, farming, asbestos, and organic solvents) and other environmental agents (e.g., smoking) and the risk of EGPA. METHODS Patients with newly diagnosed EGPA (n = 111) and general population controls (n = 333) who were matched for age, sex, and geographic area of origin were recruited at a national referral center for EGPA. Exposures were assessed using a dedicated questionnaire administered by a specialist in occupational medicine, under blinded conditions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS Exposures to silica (OR 2.79 [95% CI 1.55-5.01], P = 0.001), organic solvents (OR 3.19 [95% CI 1.91-5.34], P < 0.001), and farming (OR 2.71 [95% CI 1.71-4.29], P < 0.001) were associated with an increased risk of EGPA. Co-exposure to silica and farming yielded an OR of 9.12 (95% CI 3.06-27.19, P < 0.001), suggesting a multiplicative effect between these 2 exposures. Smoking (current and former smokers combined) was significantly less frequent among patients with EGPA compared to controls (OR 0.49 [95% CI 0.29-0.70], P < 0.001). The pack-year index was also lower among patients with EGPA (OR 0.96 [95% CI 0.94-0.98], P < 0.001). The association of silica and farming was primarily aligned with ANCA-positive EGPA, while the association of smoking status and organic solvents was primarily aligned with ANCA-negative EGPA. CONCLUSION The environment can influence susceptibility to EGPA. Exposure to silica, farming, or organic solvents is associated with an increased risk of EGPA, while smoking is associated with a lower risk. These exposures seem to have distinct effects on different EGPA subsets.

Background and objectiveSystemic small vessel vasculitides carry an increased risk of acute arterial and venous thromboembolic events (AVTE); however, this risk has not been systematically explored in Eosinophilic Granulomatosis with Polyangiitis (EGPA). This study assessed the occurrence and main risk factors of AVTE among EGPA patients as compared to the general community from the population-based Bruneck cohort.MethodsWe conducted a retrospective multicenter cohort study on 573 EGPA patients. Clinical and serological data were collected at diagnosis. Occurrence of AVTE and time to the first AVTE after EGPA diagnosis were recorded. Age-standardized event rate (SER) of AVTE as compared to the reference cohort was assessed. Cox regression was applied to identify AVTE predictors.Results129 EGPA patients (22.5%) had AVTE, considered as potentially life-threatening in 55.8%. Seventy patients experienced an AVTE prior to diagnosis (of whom 58.6% in the two years before diagnosis) and 75 following EGPA diagnosis, of whom 56% in the two subsequent years. The SER of AVTE as compared to the reference cohort was 2.10 (95% CI 1.67-2.63). This risk was particularly increased in patients with history of AVTE and with a Birmingham Vasculitis Activity Score ≥20 at diagnosis. Patients receiving immunosuppression within 2 months of diagnosis were at lower risk, while antiplatelet or anticoagulant treatment did not confer measurable benefit.ConclusionEGPA is associated with AVTE in approximately one quarter of patients, particularly around diagnosis. Immunosuppressants seemed to exert a protective effect, while anticoagulant and antiplatelet agents did not.

Background and Aims Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss Syndrome) is a rare systemic disease, included in the group of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), characterized by adult-onset asthma, blood and tissue eosinophilia with organ involvement, and small-vessel vasculitis. The pathogenesis of the disease is poorly understood, but it is likely that immunogenetic factors play a crucial role in its development. However, it has been suspected that the disease may be triggered by exogenous factors including environmental agents, infections, vaccinations, and drugs. Data about the association between individual, environmental and occupational risk factors and the development of EGPA are scarce. In this study we aimed to investigate the role of occupational agents (such as silica, farming, organic solvents and chemical agents) as well as individual agents (such as smoking habits) and their interactions, as potential risk factors for EGPA. Method The study has a case-control design. We enrolled 111 patients with EGPA and 333 healthy controls, matched for age, sex and geographical origin. Occupational history was obtained using a structured questionnaire administered by blinded specialists in occupational medicine. The exposures to non-occupational risk factors potentially predisposing to EGPA were assessed through the interview and through the examination of medical records. All exposures were considered until the time of EGPA diagnosis. Results At a multivariate logistic regression analysis, EGPA was associated with silica exposure (OR 2.26 [95% CI 1.10-4.62], p=0.026), farming (OR 2.10 [95% CI 1.19-3.73], p=0.011) and with the exposure to organic solvents (OR 2.20 [95% CI 1.14-4.2], p=0.018). There was a positive relationship between the duration of exposure to silica, chemical agents and the risk of developing EGPA (Figure 1). A multiplicative effect on risk was found for the co-exposure of silica and farming (OR 7.49 [95% CI 2.77-20.25], p Conclusion This is, to our knowledge, the first study investigating the role of environmental, occupational and individual risk factors in the development of EGPA, through the comparison of a group of EGPA patients with a group of healthy controls, matched for age, gender and geographical origin. Our results demonstrate that occupational factors may significantly contribute to the development of the disease. In particular, we found a significative association between exposure to silica, farming, organic solvents and EGPA. In addition, our findings reveal that tobacco smoking has a protective role against the disease. Further studies are necessary to investigate the biological effects of such risk factors on disease pathogenesis.

Rituximab (RTX) represents a milestone in the treatment of mixed cryoglobulinemic vasculitis (MCV). Despite usually well-tolerated, RTX may induce different types of adverse drug reactions, including exacerbation of vasculitis. Recently, RTX biosimilar CT-P10 has been approved in Europe for the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of CT-P10 in the treatment of MCV. In this multicenter open-label study, we analyzed the safety of CT-P10 in patients with MCV treated in first-line or after a shift by RTX originator. Fifty-one consecutive MCV patients (females/males 35/16, median age 68 years, median disease duration 42 months, 51% HCV positive) were included in the study between July and December 2018 and were treated with CT-P10 (group 1). Safety and effectiveness of CT-P10 were compared with a retrospective group (group 2) including 75 consecutive patients treated with RTX originator between July 2017 and July 2018. Thirty-six patients were treated with CT-P10 for the first time, while the other 15 switched from RTX originator. RTX was administrated with high or dosage schemes (375 mg/m2 four times a week apart/1000 mg twice one week apart or 250 mg/m2 twice one week apart). During a month period after the last infusion, 13/51 adverse events (AE) were observed in group 1 and 17/75 in group 2 (p not significant). Among them, 7/13 and 6/17 (in group 1 and 2, respectively) could be considered immune-mediated AE (p not significant). At univariate analysis patients with IM-AE were more frequently males (p = 0.04) and with a lower disease duration (p = 0.03), but both the parameters were not significant at logistic regression. About clinical response after 6 months by the end of the treatment, no differences were observed between patients treated with originator and CT-P10 regarding the response to the therapy. No differences were observed in safety and effectiveness between patients naive at RTX or switching from originator. Despite the higher prevalence of immune-mediated AE among patients treated with CT-P10 than originator, we have observed no significant differences between the 2 groups. The use of a low-dosage regimen is more common in group 1 than in group 2, representing a possible bias of the study, possibly influencing the appearance of AE. Considering the cost/efficacy ratio of biosimilars, their use could be helpful to treat a large number of MCV patients with an effectiveness and safety comparable to originator. Multicenter studies including a large number of patients and the new RTX biosimilars could be useful to fully elucidate the possible risk of immune-mediated adverse events with biosimilar drugs. Considering the cost/efficacy ratio of CT-P10, its use could help to treat a large number of MCV patients with an effectiveness and safety comparable to originator.

Objectives The prevalence and clinical implications of small airways involvement in SSc are still to be fully elucidated. The goal of the present work is to assess the prevalence of small airways dysfunction by impulse oscillometry and to determine whether it correlates with selected disease-related features and respiratory-related quality of life. Methods Ninety-four SSc patients and 93 healthy controls were studied by impulse oscillometry measurements. Small airways dysfunction was defined as the difference between resistance at low frequency, i.e. 5 Hz, and resistance at high frequency, i.e. 20 Hz, termed ‘R5-R20’, ⩾0.07 kPa/l/s. The St George’s Respiratory Questionnaire was used to measure health impairment in SSc patients. Radiological features of small airways disease and parenchymal abnormalities on high resolution CT chest scans were jointly assessed by two thoracic radiologists. Results Small airways dysfunction was present in 21.5% of the SSc patient cohort, with a prevalence almost 5-fold higher compared with controls, and it was significantly associated with worse respiratory-related quality of life. Radiological features consistent with small airways abnormalities were detected in 25% of SSc patients, mostly in the absence of interstitial lung changes. Combining functional and radiological evaluations, one-third of the SSc cohort showed at least one feature of small airways involvement, which was associated with the lcSSc phenotype and with longer disease duration. Conclusion The current study strengthens the hypothesis that small airway dysfunction might be a feature of SSc-related lung involvement, providing the first data on its significant impact on respiratory-related quality of life. A full assessment of lung function in SSc patients should include impulse oscillometry as a complementary technique, due to potential clinical and therapeutic implications.

Oesophageal dilatation (OD) has been implicated in the pathogenesis of interstitial lung disease (ILD) in systemic sclerosis (SSc). The aims of this study were to explore the association of the OD and SSc-ILD on chest high-resolution computed tomography (HRCT), and to establish a cutoff point for the OD suggestive for the presence of a significant lung involvement.The widest oesophageal diameter (WOD) was obtained on axial HRCT images. The parenchymal abnormalities on HRCT were coded and scored according to Warrick method. Patient-centred measures, pulmonary function tests and the single breath carbon monoxide diffusing capacity of the lung (DLco) were also obtained. Multivariate regression analysis was performed to identify factors associated with oesophageal diameter.126 subjects with SSc were included. The mean (± SD) WOD was 13.5 (± 4.2) mm, and in 76 (60.3%) participants WOD was ≥ 11 mm. SSc patients with ILD had larger oesophageal diameters than those without lung disease (19.4 vs. 14.1 mm, p 0.001). We observed a high correlation between WOD and gastro-oesophageal reflux disease questionnaire (GerdQ) (r = 0.886, p 0.001), Borg score (r = 0.705, p 0.001), and Warrick score (r = 0.614, p 0.001). WOD negatively correlated with DLco (r = - 0.508, p 0.001). Multivariate analysis demonstrated positive associations between WOD and GerdQ (p 0.0001), Borg score (p 0.0005), and total Warrick score (p = 0.019).An increased oesophageal diameter ( 11 mm) on chest HRCT is associated with pulmonary and oesophageal symptoms, more severe ILD, and lower DLco.

Background:Evidence on the efficacy of Mepolizumab (MEPO) in Eosinophilic Granulomatosis with Polyangiitis (EGPA) is scarce [1].Objectives:To assess the efficacy and safety of MEPO in real-life clinical practice.Methods:We retrospectively included patients diagnosed with EGPA and treated with MEPO (100 or 300 mg/month). MEPO efficacy was evaluated in the first 12 months in terms of systemic disease and asthma control. The occurrence of any adverse event (AE) was recorded.Results:142 patients were included (38% males; median age 46.4 (IQR 36.7-54.4); 110 and 32 on MEPO 100 and 300 mg/month, respectively). General, ear-nose-throat, pulmonary, and neurological symptoms significantly decreased during treatment (table 1). MEPO accounted for a significant reduction in the BVAS (figure 1) and for a steroid sparing effect (figure 2). The proportion of patients with asthma attacks decreased by 90% at 12 months compared to t0, and asthma-related emergency accesses dropped from 17.4% to 2.3%. Overall, 21.1% of patients had a non-serious AE.Table 1.Control of clinical symptomsMEPO beginning (t0)3 monthsp-value(t3 vs t0)6 monthsp-value(t6 vs t0)12 monthsp-value(t12 vs t0)N obsN=142N=135N=123N=89General symptoms40 (28.2%)17 (12.6%)19 (15.5%)13 (14.6%)0.002Cutaneous manifestations13 (9.2%)6 (4.4%)0.0085 (4.1%)0.0254 (4.5%)0.180ENT manifestations106 (74.7%)52 (38.5%)44 (35.8%)29 (32.6%)Pulmonary manifestations130 (91.6%)59 (43.7%)39 (31.7%)28 (31.5%)Cardiac manifestations6 (4.2%)2 (1.5%)0.0832 (1.6%)0.08300.157Intestinal manifestations10 (7.0%)1 (0.7%)0.0054 (3.3%)0.0593 (3.4%)0.059Renal manifestations5 (3.5%)3 (2.2%)0.41400.0461 (1.1%)0.317Neurological manifestations36 (25.4%)22 (16.3%)0.01218 (14.6%)0.00310 (11.2%)0.035Figure 1.Changes in BVASFigure 2.Steroid treatmentConclusion:MEPO effectively controlled systemic and respiratory EGPA symptoms in a large European cohort, with no major safety concerns.References:[1]Wechsler et al. MEPO or Placebo for Eosinophilic Granulomatosis with Polyangiitis. NEJM. 2017Disclosure of Interests:Alessandra Bettiol: None declared, Maria Letizia Urban: None declared, Federico Alberici: None declared, Carlo Agostini: None declared, Chiara Baldini: None declared, Enrica Bozzolo: None declared, Paolo Cameli: None declared, Nunzio Crimi: None declared, Stefano Del Giacco: None declared, Allyson Egan: None declared, Georgina Espigol-Frigole Consultant of: Roche and Janssen, Mara Felicetti: None declared, Marco Folci: None declared, Paolo Fraticelli: None declared, Marcello Govoni: None declared, Anna Kernder Grant/research support from: Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Carlo Lombardi: None declared, Giuseppe Lopalco: None declared, Claudio Lunardi: None declared, Aladdin J Mohammad Speakers bureau: lecture fees from Roche and Elli Lilly Sweden, PI (GiACTA study), Frank Moosig: None declared, Simone Negrini: None declared, Thomas Neumann: None declared, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Giuseppe Paolazzi: None declared, paola parronchi: None declared, Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer, Vito Racanelli: None declared, Carlo Salvarani: None declared, Maxime Samson: None declared, Jan Schroeder: None declared, Savino Sciascia: None declared, Renato A. Sinico: None declared, Benjamin Terrier: None declared, Paola Toniati: None declared, Domenico Prisco: None declared, Augusto Vaglio: None declared, Giacomo Emmi: None declared

Background and aims Hepatitis E Virus is endemic in Europe with increasing numbers of cases in recent years, also in Italy where this phenomenon has hitherto been modest. The aim of this study was to document the clinical features/natural history of locally acquired hepatitis E in our territory and explore factors which determine adverse outcome. Methods Retrospective study of patients with locally-acquired HEV (hepatitis E virus) in Marche, Italy (2011–2019). Results 1189 patients were tested for HEV with 89 confirmed cases. 81 (6.8%) had locally acquired infection; 54 (66%) were male (mean age 55.5 years) and 32 (39.5%) had active co-morbidities. 41 cases were viraemic (all HEV-3 (HEV genotype 1,2,3,4)); acute infection was found in 79 and chronic infection in 2. Forty-five cases (55%) required admission to hospital, for a total of 785 days. 4 patients developed acute on-chronic liver failure, 6 developed acute kidney injury and 8 died: all had active comorbidities. Univariate analysis showed that bilirubin, INR, immunosuppression, cirrhosis and diabetes were associated with death. On multivariant analysis the only predictor of death was the presence of diabetes (p = 0.04). Conclusions Hepatitis E in Marche Italy is mostly locally acquired and caused by HEV-3 that impacts on the morbidity and mortality particularly for fragile patients.

The aim of our study was to assess the role of videofluorography (VFG) in the evaluation of swallowing and oesophageal peristalsis in patients with systemic sclerosis (SSc).From June 2014 to September 2017, 55 consecutive SSc patients, defined according to the 2013 ACR/EULAR classification criteria, underwent VFG study using a remote-controlled digital device. In order to evaluate possible abnormalities, 18 dynamic parameters were chosen, dividing the act of swallowing into three phases: oral, pharyngeal and oesophageal phases. The following dynamic radiological findings were considered: veil motility in phonation, leakage, drooling, salivation and presence of residues in the oral cavity, pharyngeal residues, penetration, aspiration, altered motility of the upper oesophageal sphincter, efficacy of primary peristaltic contractions, oesophageal clearance capacity, reflux, oesophagitis and motility of the lower oesophageal sphincter.The VFG study was well tolerated in all patients. Dysfunctions of oesophageal motility were common and included abnormal motility of UES (12.7%) and LES (76.4%), inadequate primary peristalsis (52.7%), abnormal secondary peristalsis (29.1%) and non-peristaltic contractions (40%). A defective oesophageal clearance was observed in 69.4% of patients. Moreover, most patients presented signs of oesophageal reflux (63.6%), oesophagitis (81.8%) and hiatal hernia (80%). Pharyngeal abnormalities were less common and involved up to 50% of patients. Oesophageal dysfunction and defective clearance were associated with dcSSc and pulmonary involvement.The VFG study is a useful technique for the morphological and functional evaluation of swallowing in SSc patients.

Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by peripheral eosinophilia exceeding 1500/mm3, a chronic course, absence of secondary causes, and signs and symptoms of eosinophil-mediated tissue injury. One of the best-characterized forms of HES is the one associated with FIP1L1-PDGFRA gene rearrangement, which was recently demonstrated as responsive to treatment with the small molecule kinase inhibitor drug, imatinib mesylate. Here, we describe the case of a 51-year-old male, whose symptoms satisfied the clinical criteria for HES with cutaneous and cardiac involvement and who also presented with vasculitic brain lesions and retroperitoneal bleeding. Molecular testing, including fluorescence in situ hybridization, of bone marrow and peripheral blood showed no evidence of PDGFR rearrangements. The patient was initially treated with high-dose steroid therapy and then with hydroxyurea, but proved unresponsive to both. Upon subsequent initiation of imatinib mesilate, the patient showed a dramatic improvement in eosinophil count and progressed rapidly through clinical recovery. Long-term follow-up confirmed the efficacy of treatment with low-dose imatinib and with no need of supplemental steroid treatment, notwithstanding the absence of PDGFR rearrangement.

Background Esophageal dilation and dysfunction has been implicated in the pathogenesis of interstitial lung disease (ILD) in systemic sclerosis (SSc). Objectives The aims of this were to explore the association of the esophageal dilation and ILD on chest high-resolution computed tomography (HRCT) in patients with SSc and to establish a cut-off point for the esophageal dilation suggestive for the presence of a significant SSc-ILD. Methods The widest esophageal diameter (WED) was obtained on axial HRCT images. The parenchymal abnormalities on HRCT were coded and scored according to Warrick method. Patient-centred measures, pulmonary function tests (PFTs) and the single breath carbon monoxide diffusing capacity of the lung (DLco) were also obtained. Multivariate regression analyses were performed to identify factors associated with esophageal diameter on HRCT. Results 126 subjects with SSc were included in the analysis. The mean (±SD) WED was 13.5 (±4.2) mm, and in 76 (60.3%) partecipants WED was ≥11 mm. ILD was diagnosed 86 SSc patients (Warrick score ≥7), while in 40 subjects the lung findings were normal. SSc patients with ILD had larger mean esophageal diameter than those without lung disease (19.4 mm vs. 14.1 mm, p Conclusions In patients with SSc, an increased esophageal diameter (>11 mm) on chest HRCT is associated with pulmonary and esophageal symptoms, more severe ILD, and lower DLco. References [1] Vonk MC, van Die CE, Snoeren MM, Bhansing KJ, van Riel PL, Fransen J, et al. Oesophageal dilatation on high-resolution computed tomography scan of the lungs as a sign of scleroderma. Ann Rheum Dis2008;67:1317–21. [2] Richardson C, Agrawal R, Lee J, Almagor O, Nelson R, Varga J, Cuttica MJ, Dematte JD, Chang RW, Hinchcliff ME. Esophageal dilatation and interstitial lung disease in systemic sclerosis: A cross-sectional study. Semin Arthritis Rheum. 2016;46(1):109–4. Disclosure of Interest None declared

Background Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology, characterised by microvascular abnormalities, immune abnormalities and progressive cutaneous and internal organs fibrosis. Subclinical heart disease in SSc patients is common but difficult to detect through conventional imaging. Objectives We sought to evaluate speckle-tracking derived global longitudinal strain (GLS) as an early marker of subclinical systolic dysfunction in patients with SSc. Methods We enrolled 52 patients with SSc and 52 age and gender matched controls. Patients with structural heart disease, heart failure, atrial fibrillation or pulmonary hypertension were excluded. An echocardiographic exam was performed for all patients, and standard and specke-tracking derived variables for the systolic and diastolic function of the left ventricle (LV) and right ventricle (RV) were acquired. SSc variant, antibodies pattern, cardiovascular risk factors and involvement of other organ systems were recorded. Results Common parameters of left and right systolic function did not differ between SSc patients and controls and were on average well above the cut-off for normality (all p=NS). LV and RV GLS were significantly impaired in patients with SSc when compared to healthy controls (−19.2% vs. −21.1%; p=0.009 and −18.2% vs. −22.3%; p=0.012 respectively). In patients with SSc, GLS impairment was greater in basal segments when compared to midventricular and apical ones and homogeneous between the endo-, meso-, or epicardial layers of the RV, while LV showed an eccentric pattern with the epicardial layers mostly impaired. Using −20% as a cut-off for GLS, SSc patients had a 2.5-fold increased risk of subclinical LV systolic impairment (OR 2.5; 95% CI 1.1–5.5; p=0.027) and a 3.3-fold increased risk of subclinical RV systolic impairment when compared to age and gender matched controls (OR 3.3; 95% CI 1.4–7.7; p=0.004). Conclusions While traditional parameters are ineffective in detecting subclinical systolic impairment, a reduced GLS is common in patients with SSc and is significant for both LV and RV. While GLS impairment recognises a basal-apical gradient, transmural heart involvement seems different between RV and LV, suggesting a different mechanism of disease between the two ventricles. Disclosure of Interest None declared

To describe a single centre experience using combination therapy with rituximab (RTX) and mycophenolate mofetil (MMF) in a prospective series of systemic sclerosis (SSc) patients with pulmonary and cutaneous involvement, rapidly progressive or resistant to conventional therapy.RTX was administered in two different regimens (1000 mg fortnightly x 2 or 375 mg/m2/week for 4 consecutive weeks) at baseline and after 6 months, associated with MMF 2000 mg/day continuously. Cutaneous fibrosis was evaluated assessing modified Rodnan Skin Score (mRSS) and pulmonary involvement was evaluated performing pulmonary function tests, diffusing lung capacity for carbon monoxide and chest high-resolution computed tomography (HRCT). The radiological extension of the interstitial lung disease (ILD) at HRCT, was assessed with the conventional visual reader-based score (CoVR) and with a computerised-aided method (CaM) using a DICOM soft- ware.Eighteen SSc patients underwent combination therapy (F/M: 10/8, median age 51 years, median duration of disease 27 months). Data from fifteen patients were available at 12-month follow-up. The mRSS showed a significant improvement; a significant increase in forced vital capacity and forced expiratory volume in the first second were also observed. In addition, a signi cant reduction of the extension of ILD was detected when evaluated with CaM. No serious adverse events were observed during the follow-up period.Despite preliminary results and limited to a small number of patients, our data suggest that therapy with RTX and MMF is well tolerated, safe, and potentially effective for cutaneous and pulmonary involvement in SSc.

Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long-lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks ( p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment ( p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded ( p < 0.0001). Even with the limitations related to the small number of patients included and to the open-label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies.

Background Interstitial lung disease (ILD) and pulmonary hypertension are the leading cause of morbidity and mortality in systemic sclerosis (SSc). Although a ventilatory obstructive pattern, due to large airways impairment, has been rarely observed in SSc, a potential involvement of smaller airways (SA) has been suggested in previous reports. Recently, impulse oscillometry (IOS), a non-invasive forced oscillation technique, has been advocated as a valuable diagnostic tool for a sensitive assessment of SA. Objectives The main objectives of the present study was to investigate the prevalence of SA dysfunction by IOS in SSc patients compared to healthy controls, and to evaluate the correlation between SA dysfunction and selected radiological and clinical disease-related features. Methods Consecutive SSc patients were included in the present study according to eligibility criteria; controls were health volunteers. Both cases and controls underwent IOS measurements; cases also underwent pulmonary function tests and St. George9s respiratory questionnaire. Radiological features were assessed on the latest chest high resolution computed tomography (HRTC) scan available in the twelve months before study enrolment, evaluating for both SA signs of disease and ILD. A SA involvement at IOS was defined as R5-R20 ≥0.07 kPa/L/sec. Odds ratios and 95% confidence intervals for the IOS value was computed using multiple logistic regression models. Correlation between SA dysfunction and selected parameters were assessed using Pearson9s correlation coefficient. Results 92 cases (M/F 14/78, mean age 57.06) and 84 controls (M/F 15/69, mean age 54.28) were included in the present study. The R5-R20≥0.07 kpa/L/sec was found in 20.65% of cases and in 3.57% of controls. The OR was 7.027 (95% CI 1.99–24.72, p Conclusions A significant involvement of SA was found in a substantial proportion of SSc patients, compared to healthy controls. Moreover, this seemed to be associated with a more severe functional obstructive and restrictive impairment, and with higher PAPs values. Therefore, our findings suggests that SA may be a potential, less known, target of disease, and further studies are needed to assess prognostic and therapeutic implications of this pathologic feature. Disclosure of Interest None declared

Background Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by proliferative vascular lesions and progressive fibrosis of skin and internal organs, including the gastrointestinal tract. Gastrointestinal involvement is a very frequent complication, reported in up to 90% of SSc patients in both limited (lSSc) and diffuse (dSSc) cutaneous forms, and it is one of the earliest events. Objectives To evaluate the correlation between radiological items analyzed by videofluoroscopy swallow study and clinical patterns of patients SSc. Methods 55 patients (M/F: 6/49; median age 56y; median disease 6y, lSSc /dSSc:36/19; anti-Scl70+:21/55, ACA+:18/55, only ANA+:16/55), with a diagnosis of SSc and a history of dysphagia underwent a dynamic and morphological study of the oral, pharyngeal and esophageal phases of swallowing with videofluoroscopy. The oral and pharyngeal esophageal phases were performed in the upright position, while the esophageal phase was performed in the prone-oblique position, after administration of contrast material either in bolus form or diluted. Data were analyzed by radiologist with experience in videofluoroscopy for the evaluation of 17 videofluoroscopy items, of which, 4 concerning the oral, 4 the pharyngeal and 9 the esophageal phase, respectively. Results were expressed in a binary system. Then the main relevant videofluoroscopy findings were correlated with the principal scleroderma pattern of disease: lSSc vs dSSc; disease duration (more than 2 years) and subset of autoantibodies. Results Radiological study of swallowing disorders showed for oral phase: inadequate velar elevation in 4%, leakage in 15%, drooling in none (0%) and stasis of bolus in mouth in 4% of the patients. As for pharyngeal phase: stasis of bolus on pharyngeal in 49%, penetration in the laryngeal aditus in 53%, post-swallowing aspiration in 22%, abnormal upper esophageal sphincter behavior in 13% of the cases. Concerning esophageal phase: inadequate primary peristalsis in 53%, abnormal secondary peristalsis in 29%, non-peristaltic contractions in 40%, defects of clearance in 69%, abnormal lower esophageal sphincter behavior in 76%, hiatal hernia in 80%, esophageal reflux in 56%, esophagitis in 82% of the patients, nobody presented esophageal luminal stenosis. When we analyzed the swallowing disorders in different conditions we found that these are prevalent in patients with more than 2 year of disease, although may be found also early. Conversely, we have not found a significant prevalence between the lSSc or the dSSc, or a particular correlation with different patterns of autoantibodies. Conclusions Our study demonstrated relevant abnormalities in swallowing functions in high number of patients with SSc. Pharyngeal and esophageal phases are the most affected, also early. Swallowing disorders increase with disease progression and involve similarly the limited or the diffuse SSc. An early and detailed diagnosis, supported by a semi-quantitative analysis with the use of videofluoroscopy scores, may be useful to guide the appropriate therapeutic approach, either rehabilitative or pharmacological, and finally, to improve the patient9s quality of life. Extensive studies are necessary to confirm and transfer our data into clinical practice. Disclosure of Interest None declared

Background Tocilizumab (TCZ) is a humanized monoclonal anti-interleukin-6 receptor antibody, used for the treatment of moderate to severe rheumatoid arthritis (RA). Although TCZ has been proved to be highly effective and safe in RA patients in large clinical trials, few data are available from real-life practice [1]. Objectives To evaluate efficacy, safety and retention rate of intravenous (IV) and subcutaneous (SC) TCZ in a real-world setting. Methods We evaluated patients affected by moderate-to-severe RA and treated with TCZ from April 2010 to January 2017. Data of patients treated with IV-TCZ until January 2017 were collected retrospectively, while patients treated with either IV or SC-TCZ from January 2015 were included in a prospective cohort and assessed for disease activity, treatment discontinuation and/or onset of adverse events (AEs). DAS28-CRP, CDAI and SDAI scores were used for disease activity assessment and paired t test was used for statistical analysis. Treatment retention rate was estimated by Kaplan-Meier method. Results We evaluated 100 patients, 58 treated with IV-TCZ (8 mg/kg every 4w), 16 with SC-TCZ (162 mg every week), 26 switched from IV to SC during followup and 6 of these returned to IV-TCZ for cutaneous intolerance (80 females, median age 63 y, median duration of disease 11 y, median follow-up 16 months). Seventy-eight patients (78%) were treated with monotherapy and twenty-two (22%) in combination with methotrexate. At baseline, disease activity was severe in 87% of patients, moderate in 6% and mild or inactive in 7%; at the latest follow-up 60% of patients are in clinical remission. The mean DAS28-CRP in IV-TCZ and SW-TCZ groups considered as a whole was 4.34 at baseline and 2.71 at the latest follow-up available (p Conclusions TCZ is effective, well tolerated and safe in a population of RA patients followed in a real-life setting. No unexpected AE was observed in this large population followed for a long period. Interestingly retention rate was not affected by the administration route and in real life many patients can safely shift across different administration modalities. References Gabay C, Riek M, Hetland ML, Hauge EM, Pavelka K, Tomsic M, et al. Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study. Ann Rheum Dis. 2015 Sep 15. Disclosure of Interest None declared

A 26-year-old man was referred to our department for a 3-year history of dyspepsia responsive to oral pump-inhibitors therapy. During the last year, he underwent a gastroscopy, a colonoscopy and a computed tomography enterography that failed to reveal an underlying organic disease: a diagnosis of functional dyspepsia was made. Because of the persistence of symptoms, he came to our ambulatory where we performed an abdominal ultrasound that revealed the presence of multiple bi-lobar lesions of the liver suspected for metastases and a hypoechoic solid lesion of the pancreas body, confirmed by a contrast enhanced computed tomography. Laboratory tests showed high chromogranin A and gastrin level, and a liver biopsy was consistent with a metastatic pancreatic neuroendocrine tumor. This report aims to underlie the diffuse heterogeneous diagnostic management of some common gastrointestinal symptoms, such as dyspepsia, that are too often approached with the prescription of proton pump inhibitors. (www.actabiomedica.it)

The objective of the study is to evaluate the feasibility, safety and efficacy of home infusion of iloprost with the new portable syringe pump Infonde®, for the treatment of scleroderma-related Raynaud's phenomenon and digital ulcers.12 scleroderma patients were treated with iloprost at home, using the pump, with infusion cycles of 2 days per month (24 hours a day), for 6 months.The home treatment proved feasible since ten patients (83%) completed the entire infusion cycle, thus satisfying the feasibility target imposed by the protocol (75%). Side effects related to the device or venous access occurred in 3 out of 65 total 48-hour infusions (4.6%). They mostly consisted in phlebitis. No adverse events related to the device management were reported. Among the ten patients who completed the infusions, three showed a reduction in the number of ulcers, three maintained the same number, and four had no ulcers throughout the observation period. Patient's perception of their quality of life and wellness during home infusions, expressed with the Visual Analogue Scale (VAS) improved from 79/100 at the first infusion to 91/100 at the end of the study. All patients expressed a positive global judgment regarding this innovative method of iloprost infusion.The infusion of iloprost at home with Infonde® is feasible, safe and effective. Moreover, this approach presents potential advantages from the economic and organisational point of view. Because of the pilot design of our study, these results need to be confirmed in larger randomised trials.

We report the case of an otherwise healthy 60-year-old man presenting with fever, leucocytosis and a painful swelling of the right calf. We initially performed cultural and cytological examination of the popliteal fossa mass, but the results were disappointingly inconclusive. The subsequent development of several erythematous subcutaneous nodules, rapidly evolving to broad ulcerative lesions, prompted us to reconsider the clinical setting as a whole, which included fever, marked leucocytosis and multiple subcutaneous nodules. A biopsy of the ulcerative lesions finally led to the diagnosis of neutrophilic panniculitis, which was sustained by a hybrid myelodysplastic/myeloproliferative disorder like BCR-ABL1-negative atypical chronic myeloid leukaemia. The patient was initially treated with high-dose intravenous corticosteroids, resulting in a dramatic improvement of the skin lesions and normalisation of blood tests. Azacytidine treatment was subsequently started, and the haematological disease remained stable.

Multiple myeloma (MM) therapy should be tailored according to patient characteristics although we do not know which ones to use. By studying the characteristics of 266 real-life patients, we found performance status (PS) and Charlson Comorbidity Index (CCI) as factors affecting survival of MM patients regardless of their disease characteristics. This study might help to select patients for tailoring therapy in clinical practice.Multiple myeloma is a typical disease of the elderly but how many and which patients can be considered 'vulnerable' and how this may affect patient outcome remain unsolved issues.Data from 266 symptomatic MM patients registered at Marche MM registry from 2007 to 2010 were evaluated retrospectively. Vulnerability was defined as age75 years, PS (World Health Organization) ≥ 2, renal insufficiency (RI), bone fracture, cytopenias, and CCI score ≥ 1. Kaplan-Meier method and Cox regression were used to assess survival and associated factors. A vulnerability score (VS) incorporating significant vulnerability features was pursued to predict survival.Thirty-eight percent of patients were older than 75 years, 39% had PS = 2-4, 35% had at least 2 cytopenias, 40% had bone fracture, 14% RI, and 51% had CCI score ≥ 1. Cox regression selected international staging system (ISS) = III (hazard ratio [HR] = 1.6; P = .033), PS = 2-4 (HR = 2.5; P = .007), and CCI = 1-3 (HR = 2.1; P = .028) as factors associated with a worse overall survival. A VS including PS and CCI predicted median survival of 27 months in the 63 patients having a VS = 2 (both PS = 2-4 and CCI = 1-3) versus not reached (NR) in the 203 patients with VS = 0-1 (HR = 4.0; P.0001). In younger patients multivariate analysis selected ISS = III (HR = 5.2; P = .006) and VS = 2 (HR = 5.5; P = .024) as factors associated with shorter survival whereas only VS = 2 (HR = 3.5; P = .002) affected worse survival in elderly.Such VS proved to be a powerful prognostic factor for survival of MM patients and it might be useful to identify true vulnerable patients regardless of age.

The literature provides scant data concerning infectious complications and their effect on the outcome of patients with multiple myeloma (MM) treated with new drug combinations. Despite no substantial myelotoxic effect, thalidomide increases the risk of severe infections in patients with MM. We studied 202 patients who received regimens containing thalidomide in order to assess the time, type, outcome, and factors affecting development of severe infections, role of antibiotic prophylaxis, and effect of severe infections on final outcome. Thirty-eight patients (19%) developed a severe infection early during induction therapy and most infections were pneumonia. Only one patient died due to septic shock during neutropenia. No significant differences were reported in terms of progression-free survival (PFS) and overall survival (OS) between patients developing a severe infection and those who did not. Multivariate analysis determined a monoclonal component3 g/dL and platelets130 ,000/μL as factors associated with increased risk of severe infection. Primary antibiotic prophylaxis significantly decreased the probability of severe infection only in patients having both the above risk factors. Patients with MM receiving thalidomide combinations with high tumor burden are at high risk of developing severe infections and require primary antibiotic prophylaxis, whereas in other patients it is questionable. However, patient final outcome was not affected by infection development.

Objectives: With the aim to address the issue whether high-dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT-autologous stem cell transplantation (ASCT). Methods: Sixty-two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100–200 mg ⁄ m 2 and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group. Results and conclusions: Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT-ASCT (P = 0.0232). However, after a median follow-up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five-year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3–4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients.

Background and purposes: Neurological involvement in systemic sclerosis is unusual despite the possible cerebral localization of vascular lesions. The aim of this study was to evaluate cognitive performances and cerebral vasoreactivity in young scleroderma patients without any signs or symptoms of nervous system involvement. Methods: Sixteen scleroderma patients and 16 sex- and age-matched healthy subjects without vascular risk factors were included. A neuropsychological assessment for the evaluation of different areas of cognition was performed. For an assessment of cerebrovascular reactivity (CVR), each subject was submitted to hypercapnia with transcranial Doppler ultrasonography using the Breath-Holding Index (BHI). Results: Patients had significantly lower adjusted mean levels of performance with respect to controls in the Modified Card Sorting Test (P

There is evidence that B lymphocytes play a role in the pathogenesis of systemic sclerosis (scleroderma). Stimulatory autoantibodies targeting and activating normal human fibroblasts in vitro have been demonstrated in sera from scleroderma patients. Rituximab is a monoclonal antibody which selectively targets and depletes CD20+ B lymphocytes. We investigated the biological effects of rituximab in six patients affected by scleroderma with severe skin involvement.Six patients with severe skin fibrosis, unresponsive to immunosuppressive treatment, were treated with 375 mg/m2 per week of intravenous rituximab for a total of four doses. Serum stimulatory autoantibodies to the PDGF receptor were detected. Fibroblast activation was evaluated in fibroblasts grown from skin biopsies performed at baseline and at months 3 and 6 post-treatment. The modified Rodnan's skin score, health assessment questionnaire (HAQ) and visual analogic scale (VAS) for global wellness and B lymphocyte count were performed monthly.A significant reduction of anti-PDGF receptor autoantibodies was observed in the serum of all patients 3 months after treatment. Fibroblasts showed a significant downregulation of type I collagen gene expression and of the intracellular signalling triggered by anti-PDGFR autoantibodies. A decrease of the skin score and an improvement of disability indexes matched with the in vitro results. A single course of rituximab reduced scleroderma fibroblast activation in vitro and the serum levels of anti-PDGFR stimulatory autoantibodies.These data provide further evidence of B-cell involvement in the pathogenesis of scleroderma. Targeting B cells may be a promising treatment for scleroderma patients, and controlled clinical trials are warranted.

Objective To evaluate the efficacy and safety in the long term of a retreatment regimen with Rituximab (RTX) alone administered at clinical relapse in cryoglobulinemic vasculitis (CV). Methods Thirty patients with severe HCV-related CV, previously enrolled in the multicentre Italian trial on RTX in the treatment of CV, were retrospectively evaluated after the end of the trial. All of them were managed with RTX alone at clinical relapse, if any. Disease activity at the last available follow up was defined as complete remission (absence of active disease), partial remission (response > 50% of at least one manifestation among glomerulonephritis, peripheral neuropathy or skin ulcers) or active disease. Results The mean follow up after the first RTX cycle was 72.6 (20.4) months. After the end of the trial, 21/30 (70%) patients showed an active follow up [81.7 (10.9) months)], 3/30 (10%) lost follow up and 6/30 (20%) died. 12/21 (57.1%) patients were in complete disease remission, 5/21 (23.8%) showed a partial response and 4/21 (19%) had an active disease. 17/30 (56.7%) patients needed retreatment for relapse with a mean time to retreatment of 22.3 (12.1) months. Treatment survival of this regimen was 7.6 (0.3) years. Recurrent non-severe infections occurred in 3/30, with chronic hypogammaglobulinemia in 2/3 patients. Conclusions A long-term regimen of retreatment with RTX alone given at clinical relapse seems to be effective and safe in CV, with a low rate of infections and severe hypogammaglobulinemia.

Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression.We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments.Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts.Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.

Objective The aim of this study was to validate the classification criteria for cryoglobulinaemic vasculitis (CV). Methods Twenty-three centres were involved. New patients with CV (group A) and controls, i.e. subjects with serum cryoglobulins but lacking CV based on the gold standard of clinical judgment (group B) and subjects without cryoglobulins but with clinical features that can be observed in the course of CV (group C), were studied. Positivity of serum cryoglobulins was necessary for CV classification. Sensitivity and specificity of the criteria were calculated by comparing group A vs group B. The group A vs group C comparison was done to demonstrate the possible diagnostic utility of the criteria. Results The study included 268 patients in group A, 182 controls in group B and 193 controls in group C (small vessel vasculitis, 51.8%). The questionnaire (at least 2/3 positive answers) showed 89.0% sensitivity and 93.4% specificity; the clinical item (at least 3/4 clinical involvement) showed 75.7% sensitivity and 89.0% specificity and the laboratory item (at least 2/3 laboratory data) showed 80.2% sensitivity and 62.4% specificity. The sensitivity and specificity of the classification criteria (at least 2/3 positive items) were 89.9% and 93.5%, respectively. The comparison of group A with group C demonstrated the clinical utility of the criteria in differentiating CV from CV mimickers. Conclusion Classification criteria for CV were validated in a second, large, international study confirming good sensitivity and specificity in a complex systemic disease.

We studied the effects of 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) on differentiation, maturation, and functions of dendritic cells (DC) differentiated from human monocytes in vitro in the presence of GM-CSF and IL-4 for 7 days. Recovery and morphology were not affected by 1α,25-(OH)2D3 up to 100 nM. DC differentiated in the presence of 10 nM 1α,25-(OH)2D3 (D3-DC) showed a marked decrease in the expression of CD1a, while CD14 remained elevated. Mannose receptor and CD32 were significantly increased, and this correlated with an enhancement of endocytic activity. Costimulatory molecules such as CD40 and CD86 were slightly decreased or nonsignificantly affected (CD80 and MHC II). However, after induction of DC maturation with LPS or incubation with CD40 ligand-transfected cells, D3-DC showed marginal increases in MHC I, MHC II, CD80, CD86, CD40, and CD83. The accessory cell function of D3-DC in classical MLR was also inhibited. Moreover, allogeneic T cells stimulated with D3-DC were poor responders in a second MLR to untreated DC from the same or an unrelated donor, thus indicating the onset of a nonspecific hyporesponsivity. In conclusion, our data suggest that 1α,25-(OH)2D3 may modulate the immune system, acting at the very first step of the immune response through the inhibition of DC differentiation and maturation into potent APC.

Objective: To verify whether features of CNS involvement can be detected in SLE patients without overt neuropsychiatric manifestations.Methods: 114 SLE patients who had never received a diagnosis of neuropsychiatric lupus (never NPSLE) were studied and compared to 65 SLE patients with known neuropsychiatric involvement (NPSLE). The study relied on evaluation of neurocognitive functions by means of a battery of neuropsychological tests, on psychiatric and neuropsychological assessments and on neuroimaging studies (computed tomography, magnetic resonance, single photon emission computed tomography (SPECT)).Results: Clinical features, including disease duration/activity and pharmacological therapy, of never-NPSLE and NPSLE patients were similar. Short-term and long-term memory, visuo-spatial and verbal information processing were similarly compromised in never-NPSLE and in NPSLE patients; only attention was significantly more compromised in NPSLE patients. Psychiatric morbidity was higher than expected in never-NPSLE patients, although less than in the control neuropsychiatric group. Ischemic lesions, multiple small high intensity lesions and cortical atrophy, detected by CT and MR scans, as well as abnormal SPECT were also frequently detected in never NPSLE patients. Interestingly, left parietal and occipital area hypoperfusion by SPECT was significantly more frequent in the patients with impaired visuo-spatial intelligence and short-term memory.Conclusions: Most abnormalities detected by available diagnostic tools and characteristics of neuropsychiatric SLE are also present in non-symptomatic patients. They may derive from an unexpected widespread involvement of the CNS and are not per se sufficient, in the absence of clinical manifestations, for a diagnosis of neuropsychiatric SLE.

Bendamustine, a bi-functional alkylating agent comprising a purine-like benzimidazole ring an a nitrogen mustard group, exerts a peculiar mechanism of action if compared to most conventional alkylators and this may partially explain its effectiveness in alkylator-resistant cells. In patients with MM several studies demonstrated the efficacy and tolerability of bendamustine as monotherapy or in combination with new drugs, particularly bortezomib that was found to enhance the in vitro sensitivity of MM cells to bendamustine. These observations represented the rationale for our protocol design namely to evaluate the combination bendamustine (70 mg/m2 days 1, 8), bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD). Cycles were administered every 4 weeks up to four cycles. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Patients with relapsed/refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy were enrolled in this prospective, single-arm, open-label, phase II study conducted in 21 Italian centres. The primary endpoint was achievement of a response at least PR after four cycles of BVD and response was assessed according to to IMWG criteria. From March 2011 to June 2012, 75 patients were included. Median age was 68 years (range 41-85), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. In total, 8 of 36 evaluable patients (22%) had adverse cytogenetics. All patients had received prior treatment with new drugs, including targeted agents such as thalidomide (57%), lenalidomide (54.5%) or bortezomib (46.5%). Patients had received a median of one prior line of therapy (range 1-4), including alkylators (69%), anthracyclines (29%) and ASCT (44%). Twenty-four patients (32%) were refractory to IMIDs. The response rate ≥ PR after four cycles of BVD was 71.5%, including 11 patients with CR (16%), 13 VGPRs (18.5%) and 26 PRs (37%). Also, 14 patients (20%) had disease stabilization while 6 (8.5%) had progressive disease. Median time to response was 1.2 months (range 0.9-1.4 months). Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (54.5% vs 86.5%; P = 0.003). At a median follow-up of 12 months (range 6-24), 30 patients had progressed and 18 had died. Median TTP and PFS were 16.5 months and 15.5 months, respectively while median OS had not been reached and 78% of patients were alive at 1 year. The Cox regression analysis identified prior therapy with bortezomib plus lenalidomide as the only factor that significantly reduced TTP (9 vs 17 months; HR = 4.5; 95% CI = 1.7-12.3; P = 0.005) Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 20% and to protocol discontinuation in 10.5% of patients. The most frequent severe adverse events were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), peripheral neuropathy (8%), gastrointestinal and cardiovascular events (both 6.5%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 thrombocytopenia (22% vs 37%; p=0.042) and severe infections (7 vs 19%; p=0.047) and consequently a higher rate of therapy reduction (9% vs 34.5%; p=0.007) and therapy discontinuation (7% vs 15.5%; p=0.043). Moreover, 4/5 early deaths occurred in patients aged more than 70 years. BVD combination is an effective regimen in relapsed-refractory MM patients since it elicits rapid, high (> 70%) and good quality of response (more than a third of patients achieved CR + VGPR). Moreover, BVD combination is a feasible and well tolerated regimen provided that adapted therapy and adequate antibiotic prophylaxis are employed in patients older than 70 years. Disclosures: Offidani: Mundipharma: Honoraria, Research Funding. Off Label Use: Bendamustine.

Background Systemic Sclerosis (SSc) is a chronic systemic disease characterized by immune abnormalities, microangiopathy and progressive fibrosis of skin and internal organs. Only few therapeutic options have shown a proved disease-modifying effect for skin thickening and SSc-associated interstitial lung disease. Rituximab (RTX) and Mycophenolate Mofetil (MMF) have separately proven some evidence of efficacy and safety in clinical trials or case series Objectives Assess efficacy and safety of a combination therapy, with RTX and MMF in a cohort of SSc patients with pulmonary and cutaneous involvement rapidly progressive or resistant to conventional therapy. Methods Eligible patients were treated with RTX in two different regimens (1000 mg fortnightly x 2 or 375 mg/m2/week for 4 consecutive weeks) at baseline and after 6 months, associated with MMF 2000 mg/day. They received anti-infective prophylaxis with Valacyclovir 1000 mg and Cotrimoxazole 160/800 mg alternate days. Patients with previous malignancy or HBV, HCV or TB infection or connective overlap were excluded. Patients underwent clinical and laboratory evaluation every 3 months. Skin involvement was assessed by using the modified Rodnan Skin Score (mRSS) performed by the same physician at baseline and after 3, 6 and 12 months. Chest high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) and single-breath diffusing capacity were performed at baseline, after 6 and 12 months. The assessment of the extension of pulmonary fibrosis (PF) was analysed with the semiquantitative Warrick score and with the OsiriX quantitative computerized analysis. Data were analysed by Friedman test (GraphPadPrism V5). Results 18 SSc patients were enrolled (M/F: 8/10, median age 51y, median disease 1 y, diffuse SSc 9, limited SSc 9). Three patients withdrew from the study: one was lost to follow-up, one had a minor infusion reaction which led to RTX discontinuation and one died for different causes. The analysis includes all 15 of 18 patients who completed 12 months of follow-up. The mRSS showed a statistically significant improvement (p**=0,0036), more remarkable in patients with diffuse cutaneous SSc. Concerning PFTs there was a statistically significant increase of FVC (p**=0,0093), FEV1 (p**=0,0061), with stable values of DLCO (p=0,3375). The HRCT scan showed an improvement statistically significant evaluated with analysis by OsiriX (p*=0,0331), while the Warrick score showed a not significant trend toward improvement. No serious adverse events were observed during the follow-up. In two patients the MMF dose was reduced for mild neutropenia. Conclusions Despite preliminary and limited to a small number of patients, our results suggest that combination therapy with RTX and MMF is well tolerated, safe, and potentially effective for cutaneous and pulmonary involvement in SSc patients. Disclosure of Interest None declared

Objectives. PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. Methods. PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener’s) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with ChurgStrauss syndrome (CSS)] and in 945 healthy controls. Results. The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, � 2 = 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, � 2 = 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, � 2 = 7.258, OR = 1.98), lung involvement (P = 0.0060, � 2 = 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, � 2 = 16.567, OR = 3.73). Conclusion. The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.

Background To develop preliminary classifi cation criteria for the cryoglobulinaemic syndrome or cryoglobulinaemic vasculitis (CV). Methods Study part I developed a questionnaire for CV to be included in the formal, second part (study part II). Positivity of serum cryoglobulins was defi ned by experts as an essential condition for CV classifi cation. In study part II, a core set of classifi cation items (questionnaire, clinical and laboratory items, as agreed) was tested in three groups of patients and controls—that is, group A (new patients with the CV), group B (controls with serum cryoglobulins but lacking CV) and group C (controls without serum cryoglobulins but with features which can be observed in CV). Results In study part I (188 cases, 284 controls), a positive response to at least two of three selected questions showed a sensitivity of 81.9% and a specifi city of 83.5% for CV. This questionnaire was employed and validated in study part II, which included 272 patients in group A and 228 controls in group B. The fi nal classifi cation criteria for CV, by pooling data from group A and group B, required the positivity of questionnaire plus clinical, questionnaire plus laboratory, or clinical plus laboratory items, or all the three, providing a sensitivity of 88.5% and a specifi city of 93.6% for CV. By comparing data in group A versus group C (425 controls), the same classifi cation criteria showed a sensitivity 88.5% and a specifi city 97.0% for CV. Conclusion Classifi cation criteria for CV were developed, and now need validation.

With the aim to address the issue whether high-dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT-autologous stem cell transplantation (ASCT).Sixty-two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100-200 mg/m(2) and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group.Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT-ASCT (P = 0.0232). However, after a median follow-up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five-year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3-4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients.

Background Systemic Sclerosis (SSc) is a rare systemic disease characterized by immune abnormalities, widespread vascular injury and progressive fibrosis of skin and internal organs. Currently, only few therapeutic options have shown a proved disease-modifying effect for skin thickening and SSc-associated interstitial lung disease. Objectives To assess efficacy and safety of a combination therapy, with rituximab (RTX) and mycophenolate ofetil (MMF), in rapidly progressive or resistant to conventional therapy SSc patients with pulmonary and cutaneous involvement. Methods Patients received RTX infusion (1000 mg at day 0 and after two weeks) at baseline and after 6 months, associated with MMF 2000 mg/day from day + 15. They received anti-infective prophylaxis whit valacyclovir 1000 mg and cotrimoxazole 160/800 mg alternate days. Patients with previous malignancy or HBV, HCV or TB infection were excluded. Patients underwent clinical and laboratory evaluation every 3 months. Skin involvement was assessed by using the modified Rodnan Skin Score (mRSS). The chest high-resolution computed tomography (HRCT) and the pulmonary function tests and single-breath diffusing capacity were performed at baseline and after 6 and 12 months. Lung fibrosis at the HRCT scans was analyzed with a semi-quantitative scoring method (Fraticelli P et al. Arthritis Res Ther. 2014 Jul 8;16(4):R144). Forced vital capacity (FVC), total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (DLCO) were considered for pulmonary function assessment. Data were analyzed by Wilcoxon matched paired signed rank test. Results Eighteen SSc patients were enrolled (M/F: 8/10, median duration of disease 52 y, median age 2y, diffuse SSc 9, limited SSc 9). Two patients withdrew from the clinical study, one was lost to follow-up and the other one had a minor infusion reaction which led to RTX discontinuation. The preliminary analysis includes 12 of 18 patients who completed the 6 month follow-up. The mRSS showed a trend to improvement (p=0.1347), which, however, was not statistically significant. The improvement in patients with the diffuse cutaneous SSc was more remarkable. There was a significantly increase of FVC (p=0.0494) and TLC (p=0.0412); DLCO (p=0.7891) improved but not significantly. The HRCT pattern improved in two patients reduction of the number of lung segments with ground-glass appearance, while patients with prevalent reticular pattern or advanced honeycombing remained stable. No serious adverse events were observed during the follow-up. In one patient the MMF dose was reduced for mild neutropenia and one patient required cotrimoxazole discontinuation for mild macrocytic anemia. Conclusions Despite preliminary and limited to a small number of patients, our results suggest that combination therapy with RTX and MMF is well tolerated, safe, and potentially effective for cutaneous and pulmonary involvement in SSc patients. Disclosure of Interest None declared