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Dive into the research topics where Giulio Cavalli is active.

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Featured researches published by Giulio Cavalli.


Blood | 2014

Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Eli L. Diamond; Lorenzo Dagna; David M. Hyman; Giulio Cavalli; Filip Janku; Juvianee Estrada-Veras; Marina Ferrarini; Omar Abdel-Wahab; Mark L. Heaney; Paul J. Scheel; Nancy Feeley; Elisabetta Ferrero; Kenneth L. McClain; Augusto Vaglio; Thomas V. Colby; Laurent Arnaud; Julien Haroche

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.


Rheumatology | 2015

Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies

Giulio Cavalli; Charles A. Dinarello

The inflammatory cytokines IL-1α and IL-1β orchestrate local and systemic inflammatory responses underlying a broad spectrum of diseases. Three agents for reducing IL-1 activities are currently available. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist. Anakinra binds to the IL-1 receptor and prevents the activity of IL-1α and IL-1β. The soluble decoy receptor rilonacept and the neutralizing mAb canakinumab block IL-1β. A mAb directed against the IL-1 receptor and a neutralizing anti-human IL-1α are in clinical trials. The availability of therapies specifically targeting IL-1 unveiled the pathological role of IL-1-mediated inflammation in a broadening list of diseases. Conditions effectively treated with agents blocking IL-1 range from classic rheumatic diseases, such as RA and gout, to autoinflammatory syndromes, such as systemic JIA and FMF. However, IL-1 antagonism is also effective against highly prevalent inflammatory diseases, namely cardiovascular diseases and type 2 diabetes, conditions that are frequently encountered as co-morbidities in patients with rheumatic diseases. Thereby, IL-1 inhibition has the potential to lift the burden of disease for patients with rheumatic conditions, but also to provide clinical benefits beyond the efficacy on osteoarticular manifestations.


Annals of the Rheumatic Diseases | 2013

The multifaceted clinical presentations and manifestations of Erdheim–Chester disease: comprehensive review of the literature and of 10 new cases

Giulio Cavalli; B. Guglielmi; Alvise Berti; Corrado Campochiaro; Maria Grazia Sabbadini; Lorenzo Dagna

Objectives Erdheim–Chester disease (ECD) is a rare inflammatory disorder characterised by organ infiltration by non-Langerhans’ histiocytes. Although rare, ECD is clearly an overlooked diagnosis. No data specifically addressing the most frequent presentations of ECD at the time of onset in a large cohort of patients are currently available. Methods We reviewed all the published cases in the English literature of histologically-confirmed ECD. We excluded reports in which data regarding onset and diagnosis were not univocal, as well as repeated reports of the same case(s). We also included in the analysis 10 new unpublished patients from our cohort. We analysed the disease presentation with particular regard to the manifestations that induced patients to seek medical attention and their subsequent evolution. Results In the cumulative cohort of 259 cases, ECD predominantly presented with skeletal symptoms, diabetes insipidus, neurological and constitutional symptoms. Diabetes insipidus and constitutional symptoms, if not present at onset, seemed to only seldom develop. There were differences in ECD presentation and course among different age groups of patients. Conclusions Physicians should be aware of the extraordinarily heterogeneous clinical presentations and manifestations of ECD in order to include ECD in the differential diagnosis of several conditions.


Annals of the Rheumatic Diseases | 2015

BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease

Maria Giulia Cangi; Riccardo Biavasco; Giulio Cavalli; Greta Grassini; Elena DalCin; Corrado Campochiaro; B. Guglielmi; Alvise Berti; Vito Lampasona; Andreas von Deimling; Maria Grazia Sabbadini; Marina Ferrarini; Claudio Doglioni; Lorenzo Dagna

Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E mutation has been reported in biopsies in 19 out of 37 patients with ECD from the largest published cohort, but never found in the patients’ peripheral blood. Also, the role of the mutation in the pathogenesis of the disease has not been elucidated yet. BRAFV600E has been associated with oncogene-induced senescence (OIS), a protective mechanism against oncogenic events, characterised by the induction of proinflammatory pathways. Methods We verified the BRAF status in biopsies and peripheral blood from 18 patients with ECD from our cohort and matched controls by means of immunohistochemistry and of an ultrasensitive assay, based on the combination of a locked nucleic acid PCR and pyrosequencing. Droplet digital PCR was used to confirm the findings. We also evaluated the presence of senescence markers in ECD histiocytes. Results BRAFV600E mutation was present in all the biopsy and peripheral blood samples from patients with ECD and in none of the controls. ECD histiocytes and a fraction of circulating monocytes from patients with ECD showed signs of a constitutive activation of the MAPK pathway. Moreover, BRAF-mutated histiocytes expressed markers of OIS. Conclusions The oncogenic BRAFV600E mutation is present in biopsies and in the peripheral blood from all patients with ECD who were evaluated and is associated with OIS. These findings have significant implications for the pathogenesis, diagnosis and treatment of ECD.


Seminars in Arthritis and Rheumatism | 2015

Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab

Alvise Berti; Giulio Cavalli; Corrado Campochiaro; B. Guglielmi; Elena Baldissera; Stefano Cappio; Maria Grazia Sabbadini; Claudio Doglioni; Lorenzo Dagna

OBJECTIVE Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are systemic, necrotizing, small-vessel vasculitis associated with circulating anti-neutrophil cytoplasmic autoantibodies (ANCA), and thus called ANCA-associated vasculitides (AAV). The aim of the present study is to evaluate a potential role of interleukin (IL)-6 and its pathway in the pathogenesis of AAV and to review previous evidence of IL-6 in MPA and GPA. METHODS Blood and histological samples from 10 untreated myeloperoxidase (MPO)-ANCA/proteinase 3 (PR3)-ANCA-positive patients with active AAV were studied. Serum levels of cytokines/chemokines were evaluated by means of a Bio-Plex Multiple Cytokine Assay. IL-6 production at sites of active vasculitis was assessed by means of both immunohistochemistry and in situ hybridization techniques. We also treated a patient with MPA who was resistant or allergic to conventional treatments with a 12-month course of the IL-6 inhibitor tocilizumab and followed him up for 24 additional months. We also reviewed all the published cases in the English literature of histologically confirmed MPA or GPA, in which elevated IL-6 serum levels or intralesional IL-6 expression were reported. RESULTS IL-6 serum levels were significantly increased in patients with AAV as compared to controls (median = 51.96pg/mL; range: 34.11-84.30; versus 0.68pg/mL; range: 0.01-1.81; P < 0.005). Also, IL-6 was expressed and produced at sites of active vasculitis. Treatment with tocilizumab was able to induce a complete and sustained disease remission in a patient with severe multisystemic MPA, as well as normalization of circulating levels of IL-6-associated pro-inflammatory cytokines and chemokines. Previous evidence of IL-6 pathway activation in AAV is scarce. Increased serum levels of IL-6 were reported in seven clinical studies for a total of approximately 120 patients, mainly affected by GPA. CONCLUSION The finding of an activated IL-6 pathway in patients with AAV, together with the observed effects of tocilizumab monotherapy, provides evidence for a possible central role of IL-6 in the pathogenesis of AAV and suggests its targeting as a potential treatment.


Scandinavian Journal of Rheumatology | 2015

Efficacy and safety of biological agents in adult-onset Still's disease.

Giulio Cavalli; S Franchini; P Aiello; B Guglielmi; Alvise Berti; Corrado Campochiaro; Maria Grazia Sabbadini; Elena Baldissera; Lorenzo Dagna

Objectives: To describe the efficacy and safety of different biological agents in a large cohort of 20 patients with adult-onset Still’s disease (AOSD). Method: We retrospectively evaluated 20 patients with severe or refractory AOSD treated with at least one biological agent (anakinra, etanercept, tocilizumab, and adalimumab), followed up for at least 12 months at our Institution. We collected and analysed data on the disease course, treatment outcome, and adverse effects, and compared our data with other published series. Results: The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. In eight patients the biological agent that was first administered proved ineffective, and a switch to a different biologic was necessary. In three patients a third biologic was necessary to achieve disease control. The biologics eventually determined a clinical response in all patients. Patients with systemic disease showed better responses than patients with chronic articular disease (p < 0.05). Biological agents allowed either the withdrawal or the tapering of corticosteroid therapy (p < 0.0001) and of disease-modifying anti-rheumatic agents (DMARDs; p < 0.05). Three patients experienced herpes zoster reactivation. Conclusions: This is the longest follow-up of a cohort of AOSD patients treated with biological agents. Our data show that biologics are safe and generally effective in the long-term management of AOSD, particularly in cases with systemic disease, and suggest that a clinical response can be obtained in almost all AOSD patients, although a switch to drugs with a different mechanism of action may be necessary.


Frontiers in Immunology | 2014

Oncogene-Induced Senescence as a New Mechanism of Disease: The Paradigm of Erdheim–Chester Disease

Giulio Cavalli; Riccardo Biavasco; Bruno Borgiani; Lorenzo Dagna

Erdheim–Chester disease (ECD) is a rare form of systemic histiocytosis characterized by the diffuse infiltration of tissues by lipid-laden macrophages. As the clinical course and prognosis are highly influenced by site of disease involvement, ECD course ranges from asymptomatic to life threatening, with a reported global 5-year mortality of 30–40%. Whether ECD is an inflammatory or clonal disease in its nature has long been debated. The disease is characterized by a network of pro-inflammatory cyto/chemokines responsible for the recruitment and activation of histiocytes into ECD lesions, similarly to what reported in Langerhans cell histiocytosis (LCH). Growing evidence supports a central role of the oncogenic BRAFV600E mutation in histiocytosis pathogenesis, and suggests oncogene-induced senescence (OIS), a major protective mechanism against oncogenic events characterized by cell-cycle arrest and the induction of pro-inflammatory molecules, as the possible link between the oncogenic mutation and the observed inflammation. Indeed, ECD recapitulates in vivo the molecular events associated with OIS, i.e., cell-cycle arrest and a potent local inflammatory response. Accordingly, the infiltration of different tissues by macrophages and the inflammatory local and systemic effects observed in ECD likely represent a drawback of OIS. Therefore, these findings delineate a new conception of OIS as a new pathogenic mechanism intrinsically responsible for disease development.


Proceedings of the National Academy of Sciences of the United States of America | 2017

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance

Giulio Cavalli; Jamie N. Justice; Kristen E. Boyle; Angelo D'Alessandro; Elan Z. Eisenmesser; Jonathan J. Herrera; Kirk C. Hansen; Travis Nemkov; Rinke Stienstra; Cecilia Garlanda; Alberto Mantovani; Douglas R. Seals; Lorenzo Dagna; Leo A. B. Joosten; Dov B. Ballak; Charles A. Dinarello

Significance Interleukin 1 family member IL-37 is a naturally occurring inhibitor of inflammation. In this study, exogenous administration of recombinant human IL-37 reversed the decrease in exercise performance observed during systemic inflammation. IL-37 also increased exercise performance in healthy mice. IL-37 treatment acted through a dual mechanism of suppression of inflammation and modulation of metabolic pathways. The implications of the present findings impact on patients with chronic inflammatory diseases spanning from rheumatoid arthritis to cancer, in which fatigue is often incapacitating, and provide rationale for exploring recombinant IL-37 in the treatment of inflammation-mediated fatigue. IL-1 family member interleukin 37 (IL-37) has broad antiinflammatory properties and functions as a natural suppressor of innate inflammation. In this study, we demonstrate that treatment with recombinant human IL-37 reverses the decrease in exercise performance observed during systemic inflammation. This effect was associated with a decrease in the levels of plasma and muscle cytokines, comparable in extent to that obtained upon IL-1 receptor blockade. Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared with vehicle-treated mice (P = 0.01). Treatment with eight daily doses of IL-37 resulted in a further 326% increase in endurance running time compared with the performance level of mice receiving vehicle (P = 0.001). These properties required the engagement of the IL-1 decoy receptor 8 (IL-1R8) and the activation of AMP-activated protein kinase (AMPK), because both inhibition of AMPK and IL-1R8 deficiency abrogated the positive effects of IL-37 on exercise performance. Mechanistically, treatment with IL-37 induced marked metabolic changes with higher levels of muscle AMPK, greater rates of oxygen consumption, and increased oxidative phosphorylation. Metabolomic analyses of plasma and muscles of mice treated with IL-37 revealed an increase in AMP/ATP ratio, reduced levels of proinflammatory mediator succinate and oxidative stress-related metabolites, as well as changes in amino acid and purine metabolism. These effects of IL-37 to limit the metabolic costs of chronic inflammation and to foster exercise tolerance provide a rationale for therapeutic use of IL-37 in the treatment of inflammation-mediated fatigue.


Frontiers in Pharmacology | 2017

Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset still's disease: A multicentre retrospective observational study

Serena Colafrancesco; Roberta Priori; Guido Valesini; Lorenza Maria Argolini; Elena Baldissera; Elena Bartoloni; Daniele Cammelli; G. Canestrari; Luca Cantarini; Elena Cavallaro; Giulio Cavalli; Lucia Cerrito; Paola Cipriani; Lorenzo Dagna; Ginevra De Marchi; Salvatore De Vita; Giacomo Emmi; Gianfranco Ferraccioli; Micol Frassi; Mauro Galeazzi; Roberto Gerli; Roberto Giacomelli; Elisa Gremese; Florenzo Iannone; Giovanni Lapadula; Giuseppe Lopalco; Raffaele Manna; Alessandro Mathieu; Carlomaurizio Montecucco; Marta Mosca

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still’s disease (AOSD). Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot’s score was used to evaluate disease severity. Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot’s score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot’s score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.


Proceedings of the National Academy of Sciences of the United States of America | 2016

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Giulio Cavalli; Masahiro Hayashi; Ying Jin; Daniel Yorgov; Stephanie A. Santorico; C Holcomb; M Rastrou; Henry A. Erlich; Isak W. Tengesdal; Lorenzo Dagna; C P Neff; Brent E. Palmer; Richard A. Spritz; Charles A. Dinarello

Significance Vitiligo is a classic autoimmune disease genetically associated with SNPs in the MHC class II region. To date, the impact of HLA molecules on autoimmunity has focused on structural diversity of antigen presentation. Here, we describe the properties of a 47-nucleotide high-risk haplotype of three SNPs within an intergenic “super-enhancer” located between the HLA-DRB1 and HLA-DQA1 genes, localized by a genome-wide association study of 2,853 subjects with vitiligo. Monocytes from healthy subjects homozygous for the high-risk haplotype have increased surface expression of HLA-DR and -DQ, and peripheral blood mononuclear cells from high-risk subjects produce more IL-1β and IFN-γ upon engagement of dectin-1, mannose, and Toll-like receptors. This study underscores the importance of transcriptional regulation of HLA genes to the risk of developing an autoimmune disease. Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an “adjuvant” during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.

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Dive into the Giulio Cavalli's collaboration.

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Lorenzo Dagna

Vita-Salute San Raffaele University

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Corrado Campochiaro

Vita-Salute San Raffaele University

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Alvise Berti

Vita-Salute San Raffaele University

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Maria Grazia Sabbadini

Vita-Salute San Raffaele University

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B. Guglielmi

Vita-Salute San Raffaele University

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Charles A. Dinarello

University of Colorado Denver

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Alessandro Tomelleri

Vita-Salute San Raffaele University

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Elena Baldissera

Vita-Salute San Raffaele University

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Giacomo De Luca

Vita-Salute San Raffaele University

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Claudio Doglioni

Vita-Salute San Raffaele University

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