Fabrizio De Benedetti

Fabrizio De Benedetti
Ospedale Pediatrico Bambino Gesù | Bambino Gesù · Department of Medicine

MD, PhD, Head of Division

About

408
Publications
42,497
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13,150
Citations
Additional affiliations
January 2003 - present
January 1998 - present
Istituto Clinico Humanitas IRCCS
January 1993 - December 2003

Publications

Publications (408)
Article
Full-text available
Background To report baseline characteristics, patient reported outcomes and treatment of children with Juvenile Dermatomyositis (JDM) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods Children newly diagnosed with JDM were enrolled in the CARRA Registry from 41 pediatric rheumatology centers. Baseline patient...
Article
Objectives: To evaluate the feasibility of the autoinflammatory disease activity index (AIDAI) as a tool to assess disease activity in patients with hereditary recurrent fever syndromes (HRFs) treated with canakinumab. Methods: Patients with active colchicine-resistant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), or tum...
Article
Objectives: To develop a Pediatric Glucocorticoid Toxicity Index (pGTI), a standardized, weighted clinical outcome assessment that measures change in glucocorticoid (GC) toxicity over time. Methods: Fourteen physician experts from 7 subspecialties participated. The physician experts represented multiple subspecialties in which GCs play a major role...
Article
Cutaneous leishmaniasis (CL) is the most frequent form of leishmaniasis. The auricle is an extremely rare site for CL in the Old World. Auricular CL may be mistaken for other entities, such as relapsing polychondritis (RP). Here we report a pediatric case of Old World auricular CL mimicking RP in a child successfully treated with intralesional lipo...
Article
Background MAS is a severe, life-threatening complication of rheumatic diseases that occurs most frequently in patients with sJIA. The mainstay of treatment for MAS is high dose glucocorticoids (GCs); however, GCs do not provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morbidity and...
Article
Background Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombotic events (TEs) and/or pregnancy morbidity, in association with two consecutive positive determinations (at least 12 weeks apart) of antiphospholipid antibodies (aPLs). Several manifestations which are not considered clinical criteria of APS have been ident...
Article
CD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (pHLH and iaHLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Fl...
Article
A case of a 7-year-old girl finally diagnosed with Langerhans cell histiocytosis is presented. The differential diagnosis between Langerhans cell histiocytosis and chronic nonbacterial osteomyelitis is discussed.
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Background Social determinants of health (SDH) greatly influence outcomes during the first year of treatment in rheumatoid arthritis, a disease similar to polyarticular juvenile idiopathic arthritis (pJIA). We investigated the correlation of community poverty level and other SDH with the persistence of moderate to severe disease activity and functi...
Article
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We have recently provided new evidence for a role of p75NTR receptor and its preferential ligand proNGF in amplifying inflammatory responses in synovial mononuclear cells of chronic arthritis patients. In the present study, to better investigate how activation of the p75NTR/proNGF axis impacts synovial inflammation, we have studied the effects of p...
Article
Objective: To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (SJIA). Methods: Data from patients with SJIA enrolled in the Pharmachild registry (NCT03932344) before 30 September 2018 and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse e...
Article
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Background Pathogenic missense variants in CDC42 differentially affect protein function, causing a clinically wide phenotypic spectrum variably affecting neurodevelopment, hematopoiesis and immune response. More recently, three variants at the C-terminus of CDC42 were proposed to similarly impact protein function and cause a novel autoinflammatory...
Article
Objective To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). Methods Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition for JIA. The primary treatmen...
Article
Objective The study aimed to report a novel coronavirus disease 2019 (COVID-19)-associated multisystem inflammatory syndrome in children (MIS-C) in a neonate found to have an atypical diffuse thickening in coronary artery walls whose diagnosis required a multi-imaging approach. Study Design A neonate presented at birth with multiple organ involveme...
Article
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Background The impact of social determinants of health on children with polyarticular juvenile idiopathic arthritis (pJIA) is poorly understood. Prompt initiation of treatment for pJIA is important to prevent disease morbidity; however, a potential barrier to early treatment of pJIAs is delayed presentation to a pediatric rheumatologist. We examine...
Article
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Background We aimed to characterize etanercept (ETN) use in juvenile idiopathic arthritis (JIA) patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods The CARRA Registry is a convenience cohort of patients with paediatric onset rheumatic diseases, including JIA. JIA patients treated with ETN for w...
Article
Introduction: MAS is a severe, life-threatening complication of rheumatic diseases such as Still's disease and systemic lupus erythematosus (SLE). MAS is a form of secondary hemophagocytic lymphohistiocytosis, characterized by a hyperinflammatory state caused by immune cell dysregulation which can lead to multiorgan damage. Sustained activation and...
Article
Introduction: MAS is a severe, life-threatening complication of rheumatic diseases that occurs most frequently in patients with sJIA. The mainstay of treatment for MAS is high dose glucocorticoids (GCs); however, GCs do not always provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morb...
Article
Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hy...
Article
Objectives To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency (MKD) during the open label extension (weeks 41–113) of the randomised controlled CLUSTER trial. Methods During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was...
Article
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Background Pleural effusion in systemic lupus erythematous (SLE) is a common symptom, and recent studies demonstrated that IL-6 has a pivotal role in its pathogenesis. Case presentation We report a case of a 15 years old Caucasian boy with a history of persistent pleural effusion without lung involvement or fever. Microbiological and neoplastic ae...
Article
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Objectives: To evaluate the effect of canakinumab on health-related quality of life (HRQoL), work/school and social life of patients with autoinflammatory recurrent fever syndromes, including colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and tumour necrosis factor receptor-associated periodic syndrome, in the CLU...
Article
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Background Based on the recently developed ChRonic nonbacterial Osteomyelitis MRI Scoring tool (CROMRIS), we developed a radiological activity index (RAI-CROMRIS) to obtain a quantification of the overall bone involvement in individual patients. Methods Whole Body Magnetic Resonance Imaging (WB-MRI) images were scored according to parameters inclu...
Article
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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by a state of hyperinflammation. Blood purification techniques can blunt the inflammatory process with a rapidly relevant nonselective effect on the cytokine storm, thus potentially translating into survival benefit for these patients. In this cohort, we evaluate...
Article
Objective To evaluate in real-life the effectiveness and safety of canakinumab in Italian patients with systemic juvenile idiopathic arthritis (sJIA). Methods A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, after 6 and 12 months from star...
Article
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IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular...
Article
Background Systemic juvenile idiopathic arthritis (SJIA) is characterized by extra-articular manifestations, as fever and rash, and rarely associated by a potentially lethal complication as macrophage activation syndrome (MAS). Anakinra is a recombinant human interleukin (IL)-1 receptor antagonist whose efficacy and safety profile has been studied...
Article
Background Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such...
Article
Background: Cytokine storm syndromes are life-threatening complications which can occur in children with rheumatic conditions (macrophage activation syndrome, MAS), inherited cytotoxicity defects (primary haemophagocytic lymphohistiocytosis, pHLH) or in course of infection or malignancies (secondary HLH, sHLH). To adequately steer subsequent treatm...
Preprint
Full-text available
Background. Based on the recently developed ChRonic nonbacterial Osteomyelitis MRI Scoring tool (CROMRIS), we developed a radiological activity index (RAI-CROMRIS) to obtain a quantification of the overall bone involvement in individual patients. Methods. Whole Body Magnetic Resonance Imaging (WB-MRI) images were scored according to parameters incl...
Article
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Pansclerotic morphea (PSM) is a rare skin disease characterized by progressive stiffening of the skin with or without the typical superficial skin changes usually seen in morphea (localized scleroderma). Standard therapy, consisting of a combination of systemic glucocorticoids and methotrexate or mycophenolate mofetil, does rarely stop disease prog...
Article
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Objective To investigate the activation of the IFNγ signaling pathway in monocytes of patients with secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) and to evaluate whether levels of phosphorylated STAT1 represent a biomarker for the identification of patients at early stages of the disease. Methods Fresh wh...
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Objectives To determine subcutaneous-tocilizumab (SC-TCZ) dosing regimens for systemic juvenile idiopathic arthritis (sJIA) and polyarticular JIA (pJIA). Methods In two 52-week phase 1 b trials, SC-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 we...
Article
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Adenosine Deaminase 2 Deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regula...
Article
Objectives To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). Methods In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body...
Article
Objectives Colchicine is the main treatment for familial Mediterranean fever (FMF). Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with F...
Article
Objective To describe characteristics of children with enthesitis‐related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods All children with ERA and JPsA were identified. Demographics, clinical characteristics, and treatments were described. Tho...
Article
Objective To evaluate the impact of early treatment and IL1RN genetic variants on the response to anakinra in systemic juvenile idiopathic arthritis (sJIA). Methods Response to anakinra was defined as clinically inactive disease (CID) at 6 months, without glucocorticoids treatment. Demographic, clinical and laboratory characteristics of 56 patient...
Article
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Background: In severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) critically ill adults, hyperinflammation plays a key role in disease progression. The clinical manifestations of SARS-CoV-2 infection among children are much less severe compared with adult patients and usually associated with a good prognosis. However, hyperinflammat...
Conference Paper
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Background/Purpose: STING-Associated Vasculopathy with Onset in Infancy (SAVI) is an autoinflammatory interferonopathy caused by gain-of-function mutations in STING1, characterized by peripheral vasculopathy and interstitial lung disease. Our aim is to describe the clinical and immunological manifestations of SAVI. Methods: Clinical information on...
Article
Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling t...
Article
Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, interferon gamma (IFNy) is considered to be the key player driving the hyperinflammat...
Article
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Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Herein, we evaluated the relationship between the gut microbiome (GM) and disease phenotype by an integrated omics fused approach. In a multicenter, observational cohort study, stools from Italian JIA patients were collected at baseline, active, and inactive disea...
Article
Background: Children with systemic lupus erythematosus (SLE) frequently have kidney involvement. Lupus nephritis sometimes presents alone, without systemic SLE features, representing the so-called full-house nephropathy (FHN). Distinguishing patients with SLE or FHN has therapeutic and prognostic implications. Methods: In this retrospective obse...
Article
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Objective: Report the 2-year efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). Methods: Patients 2 to 17 years of age with active pcJIA whose treatment with methotrexate failed received 16 weeks of open-label intravenous tocilizumab in part 1 (every 4 weeks: 8 mg/kg or 10 mg/kg for bo...
Article
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We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 (IFNAR2) gene presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient’s cells, as revealed by the lack of...
Article
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Background: Few clinical trials have investigated the prevention of radiographic progression in children with juvenile idiopathic arthritis treated with antirheumatic drugs. This study aimed to investigate radiographic progression in patients with systemic juvenile idiopathic arthritis (sJIA) and patients with polyarticular-course juvenile idiopat...
Conference Paper
Full-text available
P227 A randomized, double-blind, placebo-controlled study of anakinra in pediatric and adult patients with Still’s disease L. Schanberg1, P. Nigrovic2, A. Cooper3, W. Chatham4, S. Akoghlanian5, N. Singh6, E. Rabinovich1, A. Thatayatikom7, A. Taxter8, J. Hausmann2,9, M. Zdravkovic10, S. Ohlman10, H. Andersson10, S. Cederholm10, G. Huledal10, R. Schn...
Article
Objective Evaluate changes in health‐related quality of life (HRQOL) and disability in children with systemic juvenile idiopathic arthritis (sJIA) or polyarticular juvenile idiopathic arthritis (pJIA) treated with tocilizumab. Methods Secondary analyses of two double‐blind, placebo‐controlled trials of intravenous tocilizumab in children with acti...
Article
Full-text available
Objectives To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study. Methods Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity eve...
Conference Paper
AB1059 (2020) A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ANAKINRA IN PATIENTS WITH STILL´S DISEASE L. Schanberg1, P. Nigrovic2, A. Cooper3, W. Chatham4, S. Akoghlanian5, N. Singh6, E. Rabinovich7, A. Thatayatikom8, A. Taxter9, J. Hausmann10, M. Zdravkovic11, S. Ohlman11, H. Andersson11, S. Cederholm11, M. Wikén11, R. Schneider12, F. De Benedetti13 1...
Article
Background Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease associated with mutations in the MEFV gene. Colchicine is the cornerstone of current therapy for FMF; however, a subset of patients are resistant or intolerant to it. Previously published results from the CLUSTER trial [ NCT02059291 ] demonstrated that canakinuma...
Article
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Background Adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) are rare autoinflammatory disorders associated with an activated IL-1 pathway, characterized by spiking fever, rash, arthritis, lymphadenopathy, hepatosplenomegaly and serositis. There is a growing understanding that SJIA and AOSD are one disease with di...
Article
Background MAS is a severe complication of rheumatic diseases and occurs most frequently in patients with sJIA. Data from animal models and from observational studies in patients suggest that interferon gamma (IFNy) is a driver of the hyperinflammation and hypercytokinemia observed in MAS. Objectives To assess the pharmacokinetics, efficacy, and s...
Article
Full-text available
Increased production of inflammatory cytokines and myeloid-derived suppressor cells occur in COVID-19 patients. These inversely correlated with perforin-expressing NK and CD3+T-cells. We observed a lower perforin+ NK cells number in intensive care unit (ICU) compared to non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pat...
Article
Background Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. Methods We investigated the efficacy and safety of emapalumab (a human anti–interferon-γ antibody), administered with dexamethasone, in an ope...
Article
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Background and objective Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is c...
Article
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Coronavirus disease 2019 (COVID‐19) is sweeping across the globe. Most patients have mild to moderate symptoms, but a subgroup will become severely ill. Sepsis, respiratory failure, and acute respiratory distress syndrome (ARDS) are common complications of the disease.(1) Factors associated with ICU admission and death include older age, comorbid c...
Article
In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovativ...
Article
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Objective: This open-label study evaluated the effects of combined tocilizumab (TCZ) and disease-modifying antirheumatic drugs (DMARDs) on magnetic resonance imaging (MRI) changes in synovial membrane enhancement, bone marrow edema (BME), and erosions in the wrist and hand joints of rheumatoid arthritis (RA) patients inadequately responding to DMA...
Article
Objectives: The aim of the study is to evaluate the compliance rate to secondary prophylaxis and the presence of rheumatic heart disease (RHD) in a cohort of Italian patients with acute rheumatic fever (ARF). Methods: This is a multicentre retrospective study. The patients were divided into two groups by the presence or absence at last follow-up...
Article
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Background: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Ba...