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Giorgio Costagliola,1 Emanuela De Marco,1 Francesco Massei,1 Giulia Roberti,2 Fabrizio Catena,1 Gabriella Casazza,1 Rita Consolini3 1Section of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, 56126, Italy; 2Pediatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56126, Italy; 3Section of Clinical and Laboratory Immunology, Pediatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56126, ItalyCorrespondence: Giorgio Costagliola, Section of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, 56126, Italy, Tel +39-050992841, Email giorgio.costagliola@hotmail.com; giorgio.costagliola@ao-pisa.toscana.itAbstract: Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of lymphoproliferation are represented by infectious diseases and lymphoid malignancies. However, it is increasingly recognized that lymphoproliferative features can be the presenting sign of rare conditions, including inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Among IEI, lymphoproliferation is frequently observed in autoimmune lymphoproliferative syndrome (ALPS) and related disorders, common variable immunodeficiency (CVID), activated phosphoinositide 3-kinase δ syndrome, and Epstein-Barr virus (EBV)-related disorders. Gaucher disease and Niemann-Pick disease are the most common IEMs that can present with isolated lymphoproliferative features. Notably, other rare conditions, such as sarcoidosis, Castleman disease, systemic autoimmune diseases, and autoinflammatory disorders, should be considered in the differential diagnosis of patients with persistent lymphoproliferation when infectious and malignant diseases have been reasonably ruled out. The clinical features of lymphoproliferative diseases, as well as the associated clinical findings and data deriving from imaging and first-level laboratory investigations, could significantly help in providing the correct diagnostic suspicion for the underlying etiology. This paper reviews the most relevant diseases associated with lymphoproliferation, including infectious diseases, hematological malignancies, IEI, and IEM. Moreover, some practical indications to orient the initial diagnostic process are provided, and two diagnostic algorithms are proposed for the first-level assessment and the approach to persistent lymphoproliferation, respectively.Keywords: lymphadenopathy, splenomegaly, Hodgkin lymphoma, common variable immunodeficiency, autoimmune lymphoproliferative syndrome, gaucher disease

Gian Marco Podda,1 Giovanni Casazza,2 Francesco Casella,3 Franca Dipaola,4 Emanuela Scannella,3 Ludovica Tagliabue51Medicina III, Department of Medicine, Surgery and Dentistry, San Paolo Hospital, University of Milan, Milan, Italy; 2Department of Clinical Science, "L. Sacco", University of Milan, Milan, Italy; 3Department of Internal Medicine, L. Sacco Hospital, Milan, Italy; 4Internal Medicine, Istituti Clinici di Perfezionamento Sesto San Giovanni, Italy; 5School of Hygiene and Preventative Medicine, University of Milan, Milan, ItalyBackground: Atrial fibrillation (AF) is the most common sustained arrhythmia. It occurs in 1%–2% of the general population and its prevalence increases with age. Dronedarone, a noniodinated benzofuran similar to amiodarone, was developed as an antiarrhythmic agent for patients with atrial fibrillation. The aim of our systematic review was to critically evaluate randomized controlled trials that compared treatment with dronedarone versus placebo or amiodarone in patients with atrial fibrillation.Methods: Electronic databases (MEDLINE, Embase, and Central) were searched up to November 2011 with no language restrictions. We included randomized controlled trials in which dronedarone was compared to placebo or other drugs in patients with AF. Internal and external validity was assessed.Results: We identified seven papers corresponding to eight randomized controlled trials. The DAFNE, EURIDIS/ADONIS, and ATHENA trials demonstrated a reduction of AF recurrence with dronedarone as compared to placebo in patients with nonpermanent AF. The DIONYSOS study showed that dronedarone is less effective for the prevention of recurrent AF but improved tolerability as compared to amiodarone. Considering patients with permanent AF, the ERATO trial showed that dronedarone had rate-control effects while the PALLAS study was stopped early since stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes were significantly more frequent in subjects treated with dronedarone as compared to placebo. The ANDROMEDA trial included patients with recent hospitalization for heart failure and was terminated early because of excess of deaths in the dronedarone group.Conclusion: Like most antiarrhythmic drugs, dronedarone reduces the recurrence of AF in patients with paroxysmal or persistent AF as compared to placebo. However, relapse rates in the first year of therapy are high. Moreover, dronedarone showed to be less effective than amiodarone. Finally, dronedarone should be avoided in patients with permanent AF and a high risk for cardiovascular events or severe congestive heart failure.Keywords: amiodarone, arrhythmia, cardiovascular events

Summary: Background: Pemphigus is an autoimmune bullous disease mediated by autoantibodies targeting epithelial cell–cell adhesion molecules. Predictors of relapse have not yet been clearly identified. Aims: To identify factors at diagnosis and during follow‐up that could be predictors of relapse. Methods: Clinical and immunopathological data at diagnosis, clinical remission and first relapse from patients with pemphigus vulgaris or foliaceus and at least a 36‐month follow‐up were collected retrospectively. Based on the autoantibody profile at diagnosis, three serological patient subsets were devised: (i) anti‐desmoglein (Dsg)1‐positive and anti‐Dsg3‐negative; (iii) anti‐Dsg1‐negative and anti‐Dsg3‐positive; and (iii) anti‐Dsg1‐positive and anti‐Dsg3‐positive. Results: Data from 143 patients were collected. No significant differences were found between relapsers (n = 90) and nonrelapsers (n = 53) for time to remission or for anti‐Dsg1 and anti‐Dsg3 titres at diagnosis and remission. In the analysis of all patients, a higher risk of relapse was found for a body surface area (BSA) score of 3 compared with BSA < 3 (OR = 3.30, 95% CI 1.17–9.28; P = 0.02) and for a positive titre of either anti‐Dsg1 or anti‐Dsg3 autoantibodies at remission compared with both being negative (OR = 2.42, 95% CI 1.21–4.85, P = 0.01). In patients who were anti‐Dsg3‐positive and anti‐Dsg1‐negative at diagnosis, failure to achieve anti‐Dsg3 negativity at clinical remission was a significant predictor of relapse (OR = 7.89, 95% CI 2.06–30.21; P < 0.01). Similarly, failure to achieve anti‐Dsg1 negativity at clinical remission was a significant predictor of relapse in patients with both anti‐Dsg1 and anti‐Dsg3 positivity at diagnosis (OR = 5.74, 95% CI 1.15–28.61; P = 0.03), but not in those who were anti‐Dsg1‐positive/anti‐Dsg3‐negative at diagnosis (OR = 1.08, 95% CI 0.27–4.30; P = 0.91). Conclusion: Regardless of pemphigus subtype, autoantibody titre negativity at clinical remission in patients classified based on their anti‐Dsg1 and anti‐Dsg3 profile at diagnosis and BSA were useful tools in predicting relapse. [ABSTRACT FROM AUTHOR]