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Aims Novel therapies are needed for recurrent pericarditis, particularly when corticosteroid dependent and colchicine resistant. Based on limited data, interleukin-1 blockade with anakinra may be beneficial. The aim of this multicentre registry was to evaluate the broader effectiveness and safety of anakinra in a ‘real world’ population. Methods and results This registry enrolled consecutive patients with recurrent pericarditis who were corticosteroid dependent and colchicine resistant and treated with anakinra. The primary outcome was the pericarditis recurrence rate after treatment. Secondary outcomes included emergency department visits, hospitalisations, corticosteroid use and adverse events. Among 224 patients (46 ± 14 years old, 63% women, 75% idiopathic), the median duration of disease was 17 months (interquartile range 9–33). Most patients had elevated C-reactive protein (91%) and pericardial effusion (88%). After a median treatment of 6 months (3–12), pericarditis recurrences were reduced six-fold (2.33–0.39 per patient per year), emergency department admissions were reduced 11-fold (1.08–0.10 per patient per year), hospitalisations were reduced seven-fold (0.99–0.13 per patient per year). Corticosteroid use was decreased by anakinra (respectively from 80% to 27%; P Conclusion In patients with recurrent pericarditis, anakinra appears efficacious and safe in reducing recurrences, emergency department admissions and hospitalisations.

Pulmonary arterial hypertension (PAH) carries a high morbidity and mortality burden in Systemic Sclerosis (SSc). Therefore, PAH screening and early detection are pivotal. A systematic literature review (SLR) to search for all screening tools and modalities for SSc-PAH was performed in reference to right heart catheterization as diagnostic gold standard. Papers from 2 previously published SLRs and derived from a systematic search on Pubmed, EMBASE, Web of Science for papers published from 03/10/2017 to 31/12/2018 were manually included. A total of 199 papers were reviewed and 32 were extracted, with a low bias risk according to QUADAS2. Echocardiography, pulmonary function tests, clinical features and serum biomarkers were the most frequently tools used for screening, with different parameters combined in a variable fashion, as single item or as part of composite algorithms. Among the composite algorithms, the DETECT score, ESC/ERS 2009 or 2015 guidelines, ASIG and ITINER-air algorithms were the most commonly used in a wide range of patients. In different cohorts, DETECT and ASIG showed higher sensitivity and negative predictive value than ESC/ERS 2009. In conclusion, the literature shows echocardiography as the leading screening tool for SSc-PAH. In particular, systolic pulmonary arterial pressure (sPAP) and tricuspid regurgitation velocity (TRV), both as single items or part of composite algorithms, including also serum biomarkers, clinical and functional items, are the most frequent parameters evaluated.

Objectives Recent data have shown a significant efficacy of rituximab (RTX) in SSc. An RTX biosimilar (RTX-B) is a more affordable option. We assessed the safety and efficacy of an RTX-B (CT-P10) in SSc. Methods SSc patients treated with RTX-B with at least 6 months of follow-up were retrospectively identified from six Italian referral centres. SSc patients naïve to RTX-B (RTX-Bn) or already treated with RTX originator and switched to an RTX-B (RTX-Bs) were evaluated. A comprehensive assessment of disease characteristics and organ involvement at baseline and after 6 months was obtained. Results Thirty-three SSc patients were selected: 29 (87.9%) females, mean age 51.6 years (s.d. 14.2), mean disease duration 9.8 years (s.d. 8.1); 21 (64.5%) with dcSSc, 20 (60.1%) anti-topoisomerase I, 7 (21.2%) anti-RNA polymerase III and 6 (18.2%) anti-centromere positive. Seventeen (51.5%) were RTX-Bn and 16 were on RTX-Bs (48.5%). RTX was introduced because of skin progression in 18 patients (54.5%), interstitial lung disease (ILD) worsening in 11 (33.3%) and arthritis in 12 (36.4%). All patients were previously treated with immunosuppressants. At RTX-B introduction, 21 (63.6%) patients were on concomitant immunosuppressants: 15 (71.4%) on MMF and 6 (28.6%) on MTX. Twenty-three (69.7%) were on low-dose steroids. After 6 months, a significant reduction of the modified Rodnan skin score (mRSS), 28-joint DAS and CRP was observed (P = 0.002, 0.005 and 0.008, respectively); the mRSS significantly improved both in RTX-Bn (P Conclusion Our data suggest that RTX-B can represent a cheaper option in SSc patients, as it is effective in improving skin and joint involvement and in stabilizing lung function.

ObjectiveTo describe the features of large-vessel vasculitis (LVV) as it affects the aorta and its branches in patients with relapsing polychondritis (RP).MethodsRetrospective data and systematic literature review.ResultsTwenty-one patients were identified. LVV diagnosis was subsequent to RP and associated with extrachondral involvement in the majority of patients. Supraaortic vessels were more frequently involved (82%). Fourteen patients (67%) were treated with a conventional synthetic disease-modifying antirheumatic drug (csDMARD) and 7 (33%) with a biological DMARD (bDMARD). Vascular interventional procedures were performed in 10 patients (48%). Premature death due to cardiovascular complications was reported in 3 cases (14%).ConclusionExtraaortic LVV is a serious and overlooked RP manifestation. All patients with RP should be investigated for LVV.

Phototoxic reaction is a known feature of EPP at least in part triggered by the oxidative status, complement system activation, and mast cell response. The aim of this study was to verify some aspects involved in phototoxic reaction during a season. The complement system was evaluated by C3 assay, alternative pathway by factor-B, and classical pathway by C1q; oxidative status was tested with malondialdehyde (MDA) and mast cell by IL-10 assay. The serum samples were collected in winter and summer from 19 EPP patients and 13 controls. The reaction to sun exposure within each group was monitored without any invasive treatment. In summer, C3 and factor B were higher in patients than in controls (p = 0.002 and

Ventricular arrhythmias (VAs) have never been systematically investigated in patients with myocarditis at different stages.The purpose of this study was to compare baseline and follow-up characteristics of VAs in patients with active myocarditis (AM) versus previous myocarditis (PM).A total of 185 consecutive patients (69% males, age 44 ± 15 years, left ventricular ejection fraction 49 ± 14%) with myocarditis and VA at index hospitalization, including ventricular fibrillation, ventricular tachycardia (VT), nonsustained ventricular tachycardia (NSVT), and Lown's grade ≥2 premature ventricular complexes, were enrolled. AM and PM groups were defined based on endomyocardial biopsy and cardiac magnetic resonance findings. A subset of patients (n = 46, 25%) also underwent electroanatomic mapping and VA transcatheter ablation.At presentation, AM patients (n = 123, 66%) more commonly had ventricular fibrillation (8 cases vs. 0 cases; p = 0.053), and both irregular (61% vs. 11%; p 0.001) and polymorphic VA (NSVT and VT: 19% vs. 2%; p = 0.002; premature ventricular complexes: 63% vs. 16%; p 0.001). Only in PM patients with NSVT or VT, the dominant morphology (right-bundle branch block with superior axis) was 100% predictive of abnormal LV inferoposterior substrate at both cardiac magnetic resonance and electroanatomic mapping. At 27 ± 7 months prospective follow-up, 55 patients (30%) experienced malignant VA (AM vs. PM, p = 0.385). Although a prevalence of polymorphic and irregular VA was confirmed in AM patients with persistent inflammation in follow-up (58%), a predominance of monomorphic and regular VA was found in AM patients after myocarditis healing (42%), as well as in PM patients (all p 0.001).In myocarditis patients, polymorphic and irregular VA are more common during the active inflammatory phase, whereas monomorphic and regular VA are associated with healed myocarditis.

In this paper we argue that natural resource conservation is jeopardised by the ability of users to resort to violence to appropriate resources when they become scarce. We provide evidence from a lab experiment that participants interacting in a dynamic game of common pool resource extraction reduce their cooperation on efficient levels of resource extraction when given the possibility to appropriate the resource at some cost, i.e. through conflict. Theoretically, cooperation is achievable via the threat of punishment strategies, which stop being subgame perfect in the presence of conflict. Accordingly we argue that the observed reduction of cooperation in the game's early stages in the lab is a consequence of participants (correctly) anticipating the use of appropriation when resources become scarce.

We study ethnic favoritism in a global sample and rely on nighttime light intensity to capture a broad range of preferential policies targeted towards the political leaders' ethnic homelands. We construct two panel data sets with several thousand ethnographic regions from around 140 multi-ethnic countries and annual observations from 1992 to 2013. We find robust evidence for ethnic favoritism: nighttime light becomes 7%–10% more intense in the political leaders' ethnic homelands. We document that ethnic favoritism is a global phenomenon not restricted to Africa, poor countries, or autocracies. We also provide evidence that ethnic favoritism is partly motivated by electoral concerns and more prevalent in the presence of ethnic parties.

Depression is often under-recognized in older patients, even if antidepressants (AD) are commonly prescribed, with a prevalence of use that increase with ageing [ 1 ]. Nevertheless, even if a diagnosis of depression is established, inappropriate treatment can occur [ 2 ]. Beers criteria are the most widely screening tools used to detect inappropriate prescription of drugs in people aged 65 years or more [ 3 ]. Since 2010, attempts to adapt the Beers' criteria have been made in Europe [ 4 , 5 ]. Tricyclic drugs are the ADs to be always avoided in the elderly, owing to their anticholinergic side effects, such as cognitive impairment, delirium, urinary retention and falls [ 3 ]. Selective serotonin reuptake inhibitors (SSRIs) should be used with caution because they can cause or exacerbate hyponatraemia [ 3 ]. To our knowledge no studies have been conducted on recent data collected in hospitalized older patients in order to assess the appropriateness of prescription of ADs. With this background, the objectives of this study were to investigate the prevalence of AD use and prescription appropriateness, according to the above-cited criteria, in a large cohort of older patients hospitalized in Italian internal medicine and geriatric wards from 2010 to 2017.

Background Takayasu arteritis (TAK) is a chronic large-vessel vasculitis that predominantly affects aorta and its major branches. Although it is more commonly observed in asian population, it can occur worldwide. TAK affects more frequently women in their second and third decades of life, but occurrence in patients older than 40 years is not rare1. Female to male ratio is commonly reported as 9:12. Objectives To compare clinical characteristics and pattern of vascular involvement at disease onset according to gender specificity in patients affected by TAK. Methods Data from 117 TAK patients (11 male, 106 female) diagnosed according to the aCR criteria from our Centre were retrospectively collected. Differences between men and women with regard to demographic features, diagnostic delay, signs and symptoms attributed to TAK, and arteries involved at diagnosis were compared. Data from 3 published articles describing sex differences in TAK patients were obtained3,4,5. A global analysis of these 3 cohorts plus ours (for a total of 578 patients, 108 men and 470 women) was performed. Results In our TAK cohort, age at disease onset and age at diagnosis were not significantly different between men and women. Diagnostic delay was slightly higher in men. Male patients showed higher involvement of iliac arteries (right, p=0.016; left, p=0.021); female patients suffered more frequently from upper limbs claudication (p=0.026). In the overall analysis, men had higher prevalence of arterial hypertension (p=0.007) and more frequent involvement of abdominal aorta (p=0.026), renal arteries (right, p Conclusion In TAK patients, gender has a strong influence on pattern of vascular involvement and consequently on clinical presentation. Specifically, women have higher involvement of the supradiaphragmatic vessels, whereas in men the abdominal vessels are more frequently affected. References [1] Numano, et al. Takayasu arteritis. Lancet (2000). [2] Fatos, et al. Epidemiology of Takayasu arteritis. Presse Med (2017) [3] Lim aY, et al. Gender differences in clinical and angiographic findings of patients with Takayasu arteritis. Clin Exp Rheumatol (2015) [4] Sharma BK, et al. A possible role of sex in determining distribution of lesions in Takayasu arteritis. Int J Cardiol (1998) [5] Mont’Alverne aR de S, et al. Features of the onset of Takayasu’s arteritis according to gender. Arq Bras Cardiol (2013) Disclosure of interests Alessandro Tomelleri: None declared, Corrado Campochiaro Consultant for: Dr Corrado Campochiaro received consultation honoraria from Pfizer., Silvia Sartorelli: None declared, Giulio Cavalli Consultant for: Dr Giulio Cavalli received consultation honoraria from Pfizer, Novartis and SOBI., Giacomo De Luca Speakers bureau: Pfeizer, Sobi, Elena Baldissera Consultant for: Consultation honoraria from Novartis and Rottapharm, Speakers bureau: Pfeizer, Sobi, Novartis, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from abbvie, amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI.

Background Virus-negative or “autoimmune” myocarditis(VNM) is a severe, inflammatory heart disease with a poor prognosis, and is a leading cause of inflammatory dilated cardiomyopathy(i-DCM). Therapies are limited. Preliminary data indicate that interleukin-1(IL-1) plays a key role in the initiation and maintainance of the inflammatory heart response, sustaining an auto-inflammatory cycle[1,2]. Objectives: to evaluate the efficacy and safety of anakinra(ANK) in improving Left Ventricular Ejection Fraction(LVEF) on transthoracic echocardiography(TTE) in patients with VNM. Methods Biopsy-proven VNM patients were enrolled and treated with ANK 100 mg daily subcutaneously. All patients received treatment with the maximum tolerated dose of any beta blockers and ACE-inhibitors, according to current guidelines. At baseline and 8±4 weeks after ANK therapy, all patients underwent a full evaluation with assessment of functional status(New York Heart Association[NYHA]), measurement of high-sensitive troponin T(hs-TnT) and NT-proBNP serum levels, electrocardiography(ECG), 24h-ECG-Holter, TTE and cardiac magnetic resonance(CMR). Any myocarditis-related complication, cardiovascular deaths and adverse events(AEs) was recorded during follow-up. Continuous variables were assessed with the Wilcoxon signed-rank test for non-parametric tests and a p value Results Eleven patients(F/M=5/6, mean age 46,2±12,2 years) diagnosed with EBM-proven VNM were enrolled. Nine patients received ANK as first line therapy, and in 5 cases ANK was used as monotherapy; ANK was combined with prednisone(mean dose 31,7±16,7 mg daily) in 6 patients, 5 of them were concomitantly treated with azathioprine. On EMB, 6 patients were classified as i-DCM, 3 with acute VNM e 1 with active and chronic VNM[3-4]. Clinical onset was characterized by congestive heart failure in the most cases(72.7%). The majority of patients(72.7%) was in NYHA class III-IV. Mean LV-EF on TTE at baseline was 38,7%±19,6, with comparable findings on CMR(36,45%±18,0), and 8 patients(72.7%) had a depressed LV-EF( 10% in 5 patients(45.5%) and between 5-10% in 5 cases(45.5%); only 1 patient showed a Conclusion Our pilot study supports the efficacy and safety of ANK in the treatment of inflammatory heart failure in VNM and provides the first clinical evidence to support the therapeutic blockade of IL-1 in myocarditis. References [1] De LucaG,et al.Ann Intern Med.2018;169:819-820. [2] De LucaG,et al. Front Immunol.2018;9:1335. [3] RichardsonP,et al. Circulation.1996;93:841-2. [4] AretzHT,et al. Am J Cardiovasc Pathol.1987;1:3-14. Acknowledgement Dr Giovanni Peretto and Dr Simone Sala from Unit of Arrhythmology and Cardiac Electrophysiology Disclosure of Interests Giacomo De Luca Consultant for: Dr Giacomo De Luca received consultation honoraria from Pfizer and SOBI., Corrado Campochiaro Consultant for: Dr Corrado Campochiaro received consultation honoraria from Pfizer., Giulio Cavalli Consultant for: Dr Giulio Cavalli received consultation honoraria from Pfizer, Novartis and SOBI., Silvia Sartorelli: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI.

Background The main clinical associations of anti-PM/Scl in Systemic Sclerosis (SSc) include calcinosis, joint and muscle involvement, interstitial lung disease (ILD), and, possibly, scleroderma renal crisis (1,2). A possible association of anti-PM/Scl with cancer was reported in single-centre SSc series (2,3), but was never analysed in large multicentre studies. Moreover, the characteristics of malignancies, in particular their temporal association with the onset of SSc, were not explored. Objectives To evaluate the association of anti-PM/Scl with malignancies in a large, international, multicentre cohort. Methods 16 EUSTAR centres provided data on anti-PM/Scl+ SSc patients in their cohorts (cases), and on anti-PM/Scl-negative controls, matched for sex, age at onset (±5 years), cutaneous subset, and disease duration (±24 months). Only SSc patients with age >16 years at disease onset were included in this analysis. Anti-RNA Polymerase3+ patients were not included in controls, given the known association with synchronous cancer. Malignancies diagnosed between 2 years before and after the onset of SSc were defined as “synchronous to the onset of SSc”. Results 123 anti-PM/Scl+ SSc patients and 160 matched anti-PM-Scl- controls (28% anti-Topoisomerase I, 40% anti-centromere, 32% others) were compared (Table 1): anti-Pm/Scl+ patients had a higher prevalence of myositis (p Conclusion: in this EUSTAR multicentre case control-study, the association of anti-Pm/Scl with malignancies in SSc patients could not be confirmed. Patients with older age at SSc onset seems to be at higher risk for synchronous malignancies, regardless the autoantibody status. References [1] Lazzaroni MG, et al. Ann Rheum Dis2018; 77:(Suppl 2),421-422. [2] Bruni C, et al. Rheumatology (Oxford). 2017;56:317-8. [3] Bernal-Bello D, et al. Autoimmun Rev2017;16:461-8. Acknowledgement Authors would like to thank GILS (Gruppo Italiano Lotta Sclerodermia) for the grant to support this project Disclosure of Interests Maria Grazia Lazzaroni: None declared, Stefania Zingarelli: None declared, Jeska de Vries-Bouwstra: None declared, Eric Hachulla Consultant for: Received consulting fees or other remuneration from Actelion, GSK, Pfizer, and Bayer, Elisabetta Zanatta: None declared, Simone Barsotti: None declared, Marie-Elise Truchetet: None declared, Giacomo De Luca Speakers bureau: Pfeizer, Sobi, Vanessa Smith: None declared, Ellen De Langhe: None declared, Roger Hesselstrand: None declared, Francesca Ingegnoli: None declared, Cristian Caimmi: None declared, Silvia Bellando Randone: None declared, Enrico Colombo: None declared, Angela Ceribelli: None declared, Franco Franceschini: None declared, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Paolo Airo: None declared

Background Adult-onset Still’s disease (AOSD) is a rare auto-inflammatory condition characterized by fever, arthritis, skin rash, and multi-organ inflammation. The pathogenesis of AOSD is centrally mediated by the pro-inflammatory cytokine interleukin (IL)-1β; anakinra, a recombinant inhibitor of the IL-1β receptor, has thereby become the cornerstone of biologic therapy for AOSD. More recently, a new agent blocking IL-1β has become available, that is, the monoclonal antibody canakinumab. Objectives So far, canakinumab has been used in the treatment of AOSD following failure of multiple lines of biologic therapy, including anakinra. Here, we describe the use of canakinumab as first-line biologic agent in 6 patients with AOSD, and report the highly promising results of this treatment approach. Methods Six patients with severe, DMARD-refractory AOSD received canakinumab at the approved dose of 4 mg/kg once every 4 weeks following failure of conventional treatment with corticosteroids and methotrexate. Patient characteristics and response to therapy were recorded. Results In all patients, treatment with canakinumab led to striking and rapid clinical responses, within days of initiation. Fever and skin rash disappeared first and did not recur, followed by progressive and sustained improvement in arthritis. Inflammatory organ involvement also responded to treatment: for example, we observed resolution of pericardial inflammation in two patients, as revealed by cardiac ultrasound; another patient had hepatosplenomegaly, which also reverted to normal upon treatment. A striking reduction in serum pro-inflammatory markers C-reactive protein, erythrocyte sedimentation rate, and ferritin mirrored the efficacy on clinical manifestations. These effects amounted to a significant decrease in the modified Pouchot score for measuring disease severity (average score before canakinumab treatment: 6; after: 1.25; statistical significance of difference evaluated with Mann-Whitney: p=0.02), and allowed for tapering or discontinuation of concomitant therapy: specifically, corticosteroid treatment was completely discontinued in two patients and substantially reduced in two patients, whereas methotrexate was stopped in one patient. Conclusion In this study, first-line biologic therapy of AOSD with canakinumab resulted in rapid and marked efficacy, ultimately leading to full clinical remissions in all patients, and allowing for robust steroid-sparing effects. So far, canakinumab in AOSD has mostly been used as a last line of treatment following failure of multiple other agents, including anakinra. Early treatment, as described in this study, is nevertheless advisable and may reduce chances of chronic disease and permanent damage. References [1] Cavalli G, Dinarello CA: Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology (Oxford)2015, 54(12):2134-2144. [2] Cavalli G, Franchini S, Aiello P, Guglielmi B, Berti A, Campochiaro C, Sabbadini MG, Baldissera E, Dagna L: Efficacy and safety of biological agents in adult-onset Still’s disease. Scand J Rheumatol2015, 44(4):309-314. Disclosure of Interests Giulio Cavalli: None declared, Alessandro Tomelleri: None declared, Giacomo De Luca Speakers bureau: Pfeizer, Sobi, Corrado Campochiaro Consultant for: Dr Corrado Campochiaro received consultation honoraria from Pfizer., Elena Baldissera Consultant for: Consultation honoraria from Novartis and Rottapharm, Speakers bureau: Pfeizer, Sobi, Novartis, Lorenzo Dagna: None declared

Background recent data support the use of rituximab(RTX) in Systemic Sclerosis(SSc). RTX biosimilar(RTX-B) offers a more affordable option but its efficacy and safety have not yet been evaluated. Objectives To assess the safety and efficacy of RTX-B in SSc. Methods Data about SSc patients treated with RTX-B(1gr repeated after 2 weeks) and with a follow-up ≥6 months were retrospectively collected from 5 Italian centres. Both SSc patients naive to RTX(RTX-Bn) or already treated with ≥1 course of RTX originator(RTX-O) and switched to RTX-B(RTX-Bs) were considered. A comprehensive assessment of disease features and organ involvement was available at baseline and at final follow-up for all patients. Non parametric tests were used. Results Data of 21 SSc patients(20 female, mean age 50.5±11.8 years) were collected;mean disease duration at RTX-B therapy was 7.6±4.8 yrs. Eleven patients(52%) had diffuse cutaneous SSc(dcSSc), 12(57%) were anti-topoisomeraseI+, 5 anti-RNA-polymeraseIII+ and 4 anti-centromere+. Twelve patients(57%) were RTX-Bn and 9 RTX-Bs(43%). In RTX-Bs patients, the median number of previous RTX-O courses was 3(range 1 – 8). RTX was decided because of skin progression in 11(52%), interstitial lung disease(ILD) worsening in 9(43%), arthritis in 6(29%), myocarditis and myositis in 1 patient each. All patients had been previously treated with immunosuppressants: mycophenolate mofetil(MMF) 14(67%), methotrexate(MTX) 7(33%), cyclophosphamide 6(29%), azathioprine 4(19%), tocilizumab and etanercept 1(5%) patient each. At RTX-B introduction, 14(67%) patients were on concomitant immunosuppressant: 10(48%) MMF and 4(19%) MTX; 15 patients(71%) were also on steroids(mean dose:3.1±2.1mg/day). At 6 months after RTX-B treatment, a significant reduction of the modified Rodnan skin score(mRSS), DAS28 and erythrocyte sedimentation rate(ESR) was observed in the entire cohort (p Conclusion: in agreement with previous data published on RTX-O, also RTX-B seem efficient in improving skin and joint involvement and in stabilizing lung function, either in RTX-Bn and in RTX-Bs SSc patients. Reference: [1] JordanS,et al.AnnRheumDis.2015;74(6):1188-94. Disclosure of Interests Corrado Campochiaro Consultant for: Dr Corrado Campochiaro received consultation honoraria from Pfizer., Giacomo De Luca Consultant for: Dr Giacomo De Luca received consultation honoraria from Pfizer and SOBI., Maria Grazia Lazzaroni: None declared, Silvia Laura Bosello: None declared, Maria De Santis: None declared, adriana cariddi: None declared, Carlo Selmi Grant/research support from: AbbVie, Janssen, MSD, Novartis, Pfizer, Consultant for: AbbVie, Alfa-Sigma, Biogen, Bristol-Myrs Squibb, Celgene, Eli-Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, Speakers bureau: AbbVie, Alfa-Sigma, Biogen, Bristol-Myrs Squibb, Celgene, Eli-Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, Elisa Gremese Consultant for: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Sanofi, UCB, Roche, and Pfizer, Speakers bureau: BMS, Speakers bureau: Roche, Speakers bureau: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Sanofi, UCB, Roche, and Pfizer, Paolo Airo: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI.

Background Biologic disease-modifying anti-rheumatic drugs(bDMARDs) have been showed to be effective in refractory Takayasu arteritis(TA) [1]. Data about bDMARDs drug retention rate(DRR) in TA are scarce. Objectives To investigate DRR and reasons for discontinuation of 7 bDMARDs in a real-world setting Methods TA patients fulfilling the 1990 ACR criteria and treated with ≥1 bDMARD were selected. Data about disease duration, number of bDMARDs, reasons for bDMARDs discontinuation (classified as inefficacy, toxic reactions, non-toxic reasons), concomitant conventional synthetic (cs)DMARDs were collected. Survival curves were examined by the Kaplan-Meier method and compared using a stratified log-rank test. DRR was evaluated at 24 months. Hazard ratio(HR) for concomitant csDMARDs therapy and for previous bDMARDs was performed. A comparative sub-analysis between antiTNFα drugs and tocilizumab(TCZ) was performed Results We identified 50 patients and 86 bDMARD-courses. At baseline, mean age was 39.1±12.1 years, mean disease duration was 119.5±110.1 months. No significant differences were observed in age and disease duration between the 7 groups. 31 patients were treated with 1 bDMARD, 11 with 2, 4 with 3, 2 with 5, 1 with 6, 1 with 7. Infliximab was the most frequent first-line bDMARD(78.6%). At bDMARDs initiation all patients were on prednisone(mean dose 13.5±10.3 mg), 85.2% on csDMARD(53 methotrexate, 13 azathioprine, 6 sirolimus, 3 mycophenolate-mofetil, 1 sulfasalazine). 43% of treatment courses were stopped by 24 months. Table1 summarizes DRR and reasons for treatment discontinuation for each bDMARD. Golimumab had the highest DRR(71.4%), followed by infliximab (69%), adalimumab (56.3%), abatacept (50%), tocilizumab (41.1.%), anakinra (0%) and rituximab (0%), p=0.016. Only concomitant csDMARDs therapy (HR=2.87,95%CI=1.19-6.92,p=0.019) showed positive effects on DRR. AntiTNFα drugs had significantly higher DRR compared to TCZ (67.2% vs 41.1%,p=0.028). Even in these subgroups csDMARDs(HR=3.79,95% CI=1.49-9.6,p=0.005) showed positive effects on DRR Conclusion In our TA cohort, antiTNFα agents had the highest DRR and, notably, they had a higher DRR in a head-to-head comparison with TCZ. Concomitant use of csDMARDs had a significant positive effect on bDMARDs DRR References [1] Management of large-vessel vasculitis. Salvarani C, Hatemi G. Curr Opin Rheumatol. 2019 Jan;31 Disclosure of Interests Corrado Campochiaro Consultant for: Dr Corrado Campochiaro received consultation honoraria from Pfizer., Alessandro Tomelleri: None declared, Silvia Sartorelli: None declared, Giulio Cavalli Consultant for: Dr Giulio Cavalli received consultation honoraria from Pfizer, Novartis and SOBI., Giacomo De Luca Speakers bureau: Pfeizer, Sobi, Elena Baldissera Consultant for: Consultation honoraria from Novartis and Rottapharm, Speakers bureau: Pfeizer, Sobi, Novartis, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI.

The aims of this study were to assess the prevalence of use and prescription appropriateness of drugs for peptic ulcer and gastrooesophageal reflux disease (GERD) at hospital admission and discharge. Patients aged 65 years or more hospitalized from 2010 to 2016 in 101 Italian internal medicine and geriatric wards in the context of the REPOSI register were scrutinized to assess if they were prescribed with drugs for peptic ulcer and GERD at hospital admission and discharge. Appropriateness of prescription was assessed considering the presence of specific conditions (i.e., history of peptic ulcer or gastrointestinal hemorrhages, advanced age, Helicobacter Pylori) or gastro-toxic drug combinations, according to the criteria provided by the reimbursement rules of the Agenzia Italiana del Farmaco (NOTA 1 and 48). Among 4715 enrolled patients, 3899 were discharged alive. At hospital discharge, 2412 (61.9%, 95%CI: 60.3–63.4%) patients were prescribed with drugs for peptic ulcer and GERD, a 12% of increase from hospital admission. Almost half of the patients (N = 1776, 45.6%, 95%CI: 44.0–47.1%) were inappropriately prescribed or not prescribed: among the drugs for peptic ulcer and GERD users, about 60% (1444/2412) were overprescribed, and among nonusers, 22% (332/1487) were underprescribed. Among patients newly prescribed at hospital discharge, 60% (392/668) were inappropriately prescribed. The appropriateness of drugs for peptic ulcer and GERD therapy decreased by 3% from hospital admission to discharge. Hospitalization missed the opportunity to improve the quality of prescription of this class of drug.

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Vasculitis is an inflammatory process affecting blood vessels. Based on the involvement of the endothelium or the wall of an artery or vein, the inflammatory process can cause thickening, weakening, stenosis, occlusion, aneurysmal dilation, and scarring of the vessel, limiting blood supply to tissues and leading to partial or complete organ failure. Vasculitides affecting large arteries include Takayasu arteritis (TA) and giant cell arteritis (GCA). TA is a rare disease, which is more commonly observed in parts of Asia and the Middle East and typically affects younger women. TA causes inflammation of the aorta and its main branches and may cause a broad spectrum of symptoms ranging from limb claudication to chest pain.

Benzodiazepines (BDZs) are widely prescribed in older people. The aims of the study are to assess the prevalence of inappropriate prescription of BZDs and the associated factors in acutely hospitalized older patients. Patients aged 65 years or more hospitalized from 2010 to 2017 in more than 100 Italian internal medicine and geriatric wards in the frame of the REPOSI register were included if prescribed with BDZs at hospital admission or discharge. Appropriateness of prescription was assessed according to the 2015 Beers criteria and their modified French and German versions. Among 4681 patients discharged from hospital, 15% (N = 710) were discharged with BDZs, and 62% of them (N = 441, 95% CI: 58.5%–65.6%) were inappropriately prescribed, being prescribed with BDZ to be always avoided in the elderly (45%), at higher doses than recommended (31%) or with no appropriate clinical conditions (19%). From admission to discharge the prevalence of inappropriate BDZ prescription decreased by 4%, but 62% of patients inappropriately prescribed at admission were still inappropriately prescribed at discharge. Among the 179 patients first prescribed at the time of discharge, half were inappropriately prescribed. Being female (OR 1.32, 95%CI 0.95–1.85), enrolled in REPOSI during the years 2016 and 2017 (OR 1.94, 95%CI 1.10–3.39; OR 1.57, 95%CI 0.95–2.58) and living in nursing homes (OR 2.04, 95%CI 0.95–4.37) were associated with an increased risk to be inappropriately prescribed. This study shows a high prevalence of inappropriate use of BDZ in acutely hospitalized older patients both at hospital admission and discharge.

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

Low T-cell receptor (TCR)/CD28 signaling lymphocytes are expanded in arthritis. We asked whether the down-expression of TCR-related molecules correlates with specific arthritis characteristics and if it has clinical implications. TCR-ZETA, ZAP-70 and CD28 expression was measured by flow cytometry in synovial fluid (SF) and peripheral blood (PB)-derived T cells. In PB, ZETA-downregulation in CD4+ CD28+ and consequent CD4+ CD28lowZETAlow cell expansion correlate with CRP elevation, leukocyte recruitment into SF and, primarily, disease activity (DAS). In some patients, ZETA-downregulation extends to CD8+ CD28null and/or CD8+ CD28+ cells, and this correlates with enhanced leukocyte recruitment, multiple joint involvement, and disability index (HAQ). ZETA-downregulation in CD4+ CD28+ may also lead to CD4+ CD28+ ZETAnull cell expansion, which strongly correlates with HAQ. In SF, ZETA-downregulation in CD8+ CD28null and consequent CD8+ CD28nullZETAlow/null cell expansion correlate with CRP elevation and neutrophilic influx into SF, whereas ZAP-downregulation in CD8+ CD28+ and consequent CD8+ CD28lowZAPlow cell expansion strongly correlate with HAQ and DAS. ZETA-downregulation is preponderant in SF of seronegative arthritides, with seronegative rheumatoid arthritis showing significant down-regulation in CD8+ CD28null, and non-rheumatoid arthritides showing significant down-regulation in CD4+ CD28+ . Altogether, we identified new molecular and cellular biomarkers of arthritis-related T-cell inflammation, useful for assessing arthritis activity, predicting polyarticular progression and functional impairment, characterizing seronegative arthritides, and possibly tailoring immunotherapies.

We present a case of an 18-year-old boy habitual consumer of alcohol, initially followed by a leukoplakia of the vocal cords and subsequently undergoing a Multiple Organ Dysfunction Syndrome (MODS) with hepatic, renal and nervous system involvement. We find a mutation of alcohol dehydrogenase 4.

We study the effect of institutional quality on the appropriateness of healthcare provision in Italian hospitals. We focus on cesarean section rates for first-time mothers, which is a common indicator of appropriateness in healthcare and is vulnerable to providers’ opportunistic behaviors. To identify the causal effect of institutional quality we rely on an IV strategy based on historical instruments, exploiting the idea that current differences in institutional quality across regions have been shaped by different cultural and political histories. We find that a standard deviation increase in our indicator of institutional quality leads to a decrease of about 10 percentage points in cesarean section rates. Our results are robust to different measures of institutional quality and samples.

Background: Erythropoietic Protoporphyria (EPP) is a rare inherited hematological disorder resulting from reduced activity of the ferrochelatase (FECH), which catalyzes the insertion of iron into protoporphyrin IX (PPIX) to form heme, in the last step of the biosynthetic pathway. FECH reduced activity leads to significantly elevated PPIX levels mainly in erythrocytes and subsequently in skin and liver, causing severe photosensitivity with a childhood onset and acute liver failure. Unexpectedly no iron overload is reported, on the contrary iron deficiency anemia is often observed. The mechanisms involved in this last feature of the disease are not fully understood. Aims: This study aimed to evaluate anemia and iron status in 20 EPP patients attending the Rare Disease Centre at Fondazione Ca' Granda Policlinico in Milan, Italy, from January 2009 to present. Methods: Nine females and 11 males (age 23-57 yrs.) were diagnosed by the clinical history of photosensitivity in the presence of plasma porphyrin peak at 635nm, high levels of free PPIX in the erythrocytes and feces, and detection of genetic defects in the FECH coding gene. In all patients, iron, ferritin, transferrin (Tf), Tf saturation % (TS%), haemoglobin (Hb) and mean corpuscular volume (MCV) in peripheral venous blood were measured. Hepcidin and soluble transferrin receptor (sTfr) were also determined using commercially available immunoassays. Results: The 44% (4/9) of female patients had mild microcytic anemia (Hb 10-11.9g/dl; MCV 70.6-77.7 fl; TS% 8-16) while the 64% (7/11) male patients presented microcytosis despite normal Hb and iron levels (MCV 72-78.9 fl; Hb 13.6-14.9g/dl; iron 66-168; TS% 17-52). In addition, males with microcytosis showed normal sTfr (0.98-2.80mcg/ml) and hepcidin (7.5-24ng/ml) levels compared to higher sTfr (1.45-5.76mcg/ml) and lower hepcidin levels (0.01-15ng/ml) in microcytic females. Indeed, in 7/9 females both ferritin (4-13 ng/ml) and TS% (6-18%) were also reduced suggesting iron deficiency without anemia. As expected, hecpidin levels directly correlated with iron (r2=0.334; p Conclusion: This study shows that microcytosis is a hematological feature of EPP patients also in absence of anemia and iron deficiency. Moreover, it suggests an active role of PPIX accumulation in reducing MCV probably through a toxic effect on the red blood cell membrane. Further investigations are however required to better clarify the hepcidin-independent mechanisms involved in the iron uptake down-regulation in EPP. Disclosures No relevant conflicts of interest to declare.

Objective Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients. Methods We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered. Results We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P = .027) and micro-thrombosis (P, Highlights • We assessed and accurately described peripheral microvasculature in COVID-19 patients through nailfold videocapillaroscopy. • Capillary alterations at the nailfold bed suggest a broad COVID-related microvascular involvement. • Different alterations in acutely-ill and recovered patients resemble a transition from acute to post-acute injury.

We thank Prof Ferraccioli for his positive comments on our open-label trials with sarilumab, tocilizumab, anakinra and mavrilimumab in patients with severe hyperinflamed COVID-191–4 and for remarking the unprecedented opportunity offered by our studies to better understand the relative contribution of different targetable inflammatory pathways to the pathogenesis of severe COVID-19.5 The study designs we adopted should be definitely interpreted in light of the scientific data that progressively became available and of the course of the pandemic wave that struck Northern Italy and our Institution. Between 24 February and 22 May 2020, San Raffaele Hospital (Milan, Italy) admitted more than 1000 patients with COVID-19.6–8 Intriguingly, the clinical phenotype of admitted patients changed over time and the severity of the disease progressively varied in parallel with outbreak exhaustion.6 When our hospital was first hit by the pandemic, accumulating evidence from China was pointing at interleukin (IL)-6 as a master regulator of the cytokine storm occurring in severe COVID-19.9 Tocilizumab was, therefore, first used as a potential treatment2 and subsequently replaced by intravenous sarilumab due to sudden shortage of the drug.1 As described in …

We have read with interest the article by Cohen-Aubart et al 1 reporting the efficacy of infliximab in the treatment of Erdheim-Chester disease (ECD), a rare non-Langerhans histiocytosis. The anti-Tumor Necrosis Factor-α agent demonstrated a variable degree of efficacy, suggesting that infliximab might represent a therapeutic option for moderately severe ECD cases; similar results had been observed with anakinra.2 3 Nonetheless, following the identification of causative mutations along the mitogen-activated protein kinase(MAPK) pathway,4 severe forms of ECD are currently treated with targeted small molecule agents. Specifically, the BRAF inhibitor vemurafenib and the MAPK or extracellular-signal regulated kinase (MEK) inhibitor cobimetinib have been successfully used to treat life-threatening forms of ECD. Although life-saving, these drugs are associated with severe toxicity, which often mandates treatment discontinuation.5 …

Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by xanthogranulomatous tissue infiltration by foamy histiocytes. Fibrosis, a histologic hallmark of ECD, is responsible for lesion growth and clinical manifestations. Unraveling molecular fibrotic pathway in ECD would allow the identification of new pharmacologic targets. In this study, we evaluated serum and tissue samples from a large cohort of ECD patients focusing on two major pro-fibrotic mediators, TGF-β1 and chemokine ligand 18 (CCL18). We found a marked increase in CCL18 but not TGF-β1 levels in serum and lesions of ECD patients (p < 0.001), independently of treatment status and consistently over time. Using a linear mathematical model, we also found that elevated CCL18 serum levels correlate with both number and severity of disease localizations. These findings suggest the involvement of CCL18-induced fibrosis in ECD pathogenesis, providing a rationale for exploring CCL18 inhibition as a treatment for progressive fibrosis in ECD.

Myocarditis is defined by WHO as an inflammatory disease affecting the myocardium, diagnosed by endomyocardial biopsy (EMB) using established histological, immunological, and immunohistochemical criteria; it may be idiopathic, infectious, or autoimmune (1–4). A wide variety of histological myocarditis patterns have been described according to the diverse etiologies and to the stage of the disease at the time of EMB ascertainment. Viral infections represent the most common cause in Europe and North America (5). Different viral genomes can be detected in the myocardium of patients with myocarditis and dilated cardiomyopathy (DCM) using molecular techniques (6–14). When no infectious agents are identified on EMB and other known causes are excluded, autoimmune myocarditis (AMy) is the presumed etiology (15). These so-called “autoimmune myocarditis” or “virus-negative myocarditis” may occur as a distinct disease with exclusive cardiac involvement, or in the context of systemic autoimmune or inflammatory disorders with extracardiac involvement (5, 16–23). It is likely that several etiologic types of myocarditis confluence in a common immune-mediated pathogenic process leading to chronic inflammation and tissue damage. Irrespective of triggering agents, acute inflammation may progress to subacute and chronic stages and eventually result in tissue remodeling, fibrosis, contractile dysfunction, and finally DCM (4, 6, 8, 24–29). Besides contractile dysfunction, both early myocardial inflammation and late fibrotic changes play a critical role in the development of the arrhythmic burden, which makes myocarditis one of the leading causes of sudden death (19, 27–31). Clearly, treatment interventions effectively curbing the acute inflammatory process at an early stage can prevent late cardiac remodeling and improve patient’s outcome. Emerging evidence on the pathogenic mechanisms underlying cardiac inflammation is paving the way to novel, promising treatment strategies for myocarditis.

International audience; This paper documents the effects of the recent civil war in the Democratic Republic of Congo on mortality both in utero and during the first year of life. It instruments for conflict intensity using a mineral price index, which exploits the exogenous variation in the potential value of mineral resources generated by changes in world mineral prices to predict the geographic distribution of the conflict. Using estimates of civil war exposure on mortality across male and female newborn to assess their relative health, it provides evidence of culling effect (in utero selection) as a consequence of in utero shocks.

In their article on immune checkpoint inhibitor (ICI)–related cardiotoxicity, Escudier et al1 elegantly summarized the clinical features, management, and outcomes of cancer patients from 2 different cardio-oncology centers who developed immune-related cardiac-side effects after treatment with ICIs. There is presently no clear consensus for diagnosing ICI-related cardiotoxicity, which results in remarkable diagnostic heterogeneity. As recently reported,2 immune-mediated myocarditis is the most plausible pathological mechanism by which ICIs can cause cardiotoxicity. At present, the diagnostic gold standard for myocarditis is …

To the Editor: Tselios, et al reported in their recent study that patients with systemic lupus erythematosus (SLE) who receive prolonged antimalarial (AM) treatment are at increased risk for elevated cardiac biomarkers [brain natriuretic peptide (BNP) and high-sensitivity cardiac troponin I (HS-cTnI)], particularly when persistently elevated creatine phosphokinase (CPK) is present1. Among a well-characterized SLE cohort of 179 patients, the authors found that 16 (all without cardiac disease, renal failure, or pulmonary arterial hypertension) presented an increase of at least 1 cardiac biomarker. Prolonged AM use (> 5.6 yrs) was found to be associated with these laboratory abnormalities, regardless of age and SLE disease duration1. Regarding the potential reason underlying these findings, the authors speculated that AM deposition in muscle tissue (expressed with chronic CPK elevation) could not be restricted to skeletal muscles, and the drug could also accumulate within the myocardium. Therefore, they proposed the evaluation of these cardiac biomarkers as a screening tool for patients with SLE receiving AM … Address correspondence to Dr. G. De Luca, Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy. E-mail: deluca.giacomo{at}hsr.it

We document that the spread of the Mafia in Sicily at the end of the 19th century was in part caused by the rise of socialist Peasant Fasci organizations. In an environment with weak state presence, this socialist threat triggered landowners, estate managers, and local politicians to turn to the Mafia to resist and combat peasant demands. We show that the location of the Peasant Fasci is significantly affected by a severe drought in 1893, and using information on rainfall, we estimate the impact of the Peasant Fasci on the location of the Mafia in 1900. We provide extensive evidence that rainfall before and after this critical period has no effect on the spread of the Mafia or various economic and political outcomes. In the second part of the article, we use this source of variation in the strength of the Mafia in 1900 to estimate its medium-term and long-term effects. We find significant and quantitatively large negative impacts of the Mafia on literacy and various public goods in the 1910s and 20s. We also show a sizable impact of the Mafia on political competition, which could be one of the channels via which it affected local economic outcomes. We document negative effects of the Mafia on longer-term outcomes (in the 1960s, 70s, and 80s) as well, but these are in general weaker and often only marginally significant. One exception is its persistent and strong impact on political competition.

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

We show that armed conflict in Uganda affects social capital as measured by trust and associational membership. Relying on three rounds of nationally representative individual-level data bracketing a large number of violent events, we find that self-reported generalized trust and associational membership decreased during the conflict in districts in which violent events took place. But we also find evidence for a rapid recovery of social capital in the aftermath of violence. Results from a variety of identification strategies, including difference-in-difference and instrumental variable estimates, suggests that these relationships are causal. ispartof: Oxford Economic Papers vol:67 issue:3 pages:661-686 status: published

We study the impact of organized crime on electoral competition. Assuming that the mafia is able to bring votes to the supported party in exchange of money, we show that (i) the strongest party is willing to pay the highest price to secure mafia services; (ii) the volume of electoral trade with the mafia increases with political competition and with the efficiency of the mafia. Studying in detail parliamentary elections in Sicily for the period 1946- 1992, we document the significant support given by the Sicilian Mafia to the Christian Democratic party, starting at least from the 1970s. This is consistent with our theoretical predictions, as political competition became much tighter during the 1970s and the Sicilian mafia experienced an extensive centralization process towards the end of the 1960s, which increased substantially its control of the territory. We also provide evidence that in exchange for its electoral support the mafia got economic advantages for its activities in the construction industry.

Introduction: Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by infiltration of aberrant macrophages into multiple tissues and organs causing rampant inflammation and fibrosis. The clinical severity and the nuances of disease pathogenesis must be considered when pondering different treatment strategies for the individual patient. Areas covered: Interferon-α has long represented the first-line treatment for ECD, but its preeminence may be reappraised in the future as new effective medications become available. For example, alternative treatment options include cytokine-blocking agents, which dampen local and systemic inflammation. Of crucial importance, recent evidence indicates that deregulated activation of the mitogen-activated protein kinase (MAPK) pathway due to oncogenic mutations in the BRAF, NRAS, PIK3CA, and MAP2K1 genes is central to the pathogenesis of ECD. These advances in the molecular understanding of ECD as an inflammatory myeloid neoplasm translated into the therapeutic use of small-molecule RAF and MEK inhibitors, with unprecedented results in terms of clinical efficacy. Expert opinion: In the future, the development of ERK inhibitors holds tremendous promise for the treatment of ECD. Combination therapy with small-molecule plus anti-inflammatory agents may prove more beneficial than either treatment alone. New drugs against fibrosis, not amenable to treatment with currently available strategies, remain an unmet clinical need.

Background: Leukoencephalopathies with prominent involvement of cerebellum and brainstem, henceforward called prominent infratentorial leukoencephalopathies (PILs), encompass a variety of inherited and acquired white matter diseases. Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis likely under-diagnosed as cause of adult PIL. Methods: We reviewed the clinical and laboratory information of ten consecutive sporadic adult patients with PIL of unknown origin, who were investigated for ECD. Results: There were seven males and three females; mean age at clinical onset was 49.6 years (range 38–59); cerebellar ataxia with or without other neurological symptoms was the only or the main clinical manifestation; diabetes insipidus was present in three individuals. Eight patients had white matter focal supratentorial abnormalities, in addition to the infratentorial white matter changes. Six out of eight patients had spinal cord lesions. Thoraco-abdominal CT showed periaortic sheathing in two patients, whole-body FDG-PET revealed increased glucose uptake in the long bones of the legs in five patients, brain FDG-PET showed overt infratentorial hypermetabolism in one patient. In eight patients, ECD was confirmed by bone scintigraphy, pathological data, or both. Two ECD patients treated with vemurafenib showed a marked improvement of neurological symptoms and brain MRI abnormalities at 1 year follow-up. Conclusions: Symptoms of PIL can be the only clinical manifestation of ECD. Adult patients with PIL of unknown origin should undergo investigations aimed at unveiling ECD, including bone scintigraphy and whole-body FDG-PET. The early diagnosis allows starting disease-modifying therapies of an otherwise life-threatening disease.

We document that the spread of the Mafia in Sicily at the end of the 19th century was in part shaped by the rise of socialist Peasant Fasci organizations. In an environment with weak state presence, this socialist threat triggered landholders, estate managers and local politicians to turn to the Mafia to resist and combat peasant demands. We show that the location of the Peasant Fasci is significantly affected by an exceptionally severe drought in 1893, and using information on rainfall, we establish the causal effect of the Peasant Fasci on the location of the Mafia in 1900. We provide extensive evidence that rainfall before and after this critical period has no effect on the spread of the Mafia or various economic and political outcomes. In the second part of the paper, we use the source of variation in the location of the Mafia in 1900 to estimate its medium-term and long-term effects. We find significant and quantitatively large negative impacts of the Mafia on literacy and various public goods in the 1910s and 20s. We also show a sizable impact of the Mafia on political competition, which could be one of the channels via which it affected local economic outcomes. We document negative effects of the Mafia on longer-term outcomes (in the 1960s, 70s and 80s) as well, but these are in general weaker and often only marginally significant. One exception is its persistent and strong impact on political competition.

We estimate the impact of geo-located mining concessions on the number of conflict events recorded in the Democratic Republic of the Congo between 1997 and 2007. Instrumenting the variable of interest with historical concessions interacted with changes in international prices of minerals, we unveil an ecological fallacy: whereas concessions have no effect on the number of conflicts at the territory level (lowest administrative unit), they do foster violence at the district level (higher administrative unit). We develop and validate empirically a theoretical model where the incentives of armed groups to exploit and protect mineral resources explain our empirical findings. © Oxford University Press 2013. All rights reserved. ispartof: OXFORD ECONOMIC PAPERS-NEW SERIES vol:66 issue:3 pages:721-749 ispartof: location:Wageningen University, Wageningen status: published