IL-1 BLOCKADE IN PAEDIATRIC RECURRENT PERICARDITIS: A MULTICENTRIC RETROSPECTIVE STUDY OF THE ITALIAN COHORT

2019

Introduction: Acute pericarditis is an inflammatory condition causing the occurrence of pericardial effusion. In a third of patients, the disease is recurrent. First line treatment of idiopathic pericarditis consists in non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine; glucocorticoids represent the second line treatment in resistant or intolerant cases. A recent clinical trial has enlightened the effectiveness of anakinra in adults and paediatric patients with colchicine-resistant recurrent pericarditis. Objectives: To describe the clinical characteristics and response to treatment in a cohort of paediatric patients with recurrent pericarditis treated with IL inhibitors. Method…

Anakinra drug retention rate and predictive factors of long-term response in systemic juvenile idiopathic arthritis and adult onset still disease

2019

Background and Objective: Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD. Patients and Methods: This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers. Results: The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month of follow-up was 7…

Proceedings Of The 23Rd Paediatric Rheumatology European Society Congress: Part Two

2017

Are Kawasaki Disease and Pediatric Multi-Inflammatory Syndrome Two Distinct Entities? Results from a Multicenter Survey During SARS-CoV-2 Epidemic in…

2020

Background: There is mounting evidence on the existence of a childhood multi-inflammatory syndrome related to SARS-CoV-2, sharing similarities with Kawasaki Disease (KD).  Methods: On April 24th,2020 the Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD or KD-like disease. Classification was: 1) classical and incomplete KD, named Kawasaki Disease Group (KDG); 2) KD-like multi-inflammatory syndrome, named KawaCOVID Group (KCG). Demographic, clinical, and laboratory data, treatment information, and patients’ outcome were collected in an online anonymized database (RedCAPO). Chi square test or exact Fisher test and non parametric W…

Development and implementation of the AIDA international registry for patients with Still's disease

2022

ObjectiveAim of this paper is to present the design, construction, and modalities of dissemination of the AutoInflammatory Disease Alliance (AIDA) International Registry for patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), which are the pediatric and adult forms of the same autoinflammatory disorder.MethodsThis Registry is a clinical, physician-driven, population- and electronic-based instrument implemented for the retrospective and prospective collection of real-world data. The collection of data is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain evidence drawn from routine patients' management. The co…

Development and Implementation of the AIDA International Registry for Patients With VEXAS Syndrome

2022

ObjectiveThe aim of this paper is to present the AutoInflammatory Disease Alliance (AIDA) international Registry dedicated to Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, describing its design, construction, and modalities of dissemination.MethodsThis Registry is a clinical, physician-driven, population- and electronic-based instrument designed for the retrospective and prospective collection of real-life data. Data gathering is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain real-world evidence for daily patients' management. The Registry may potentially communicate with other on-line tools dedicated to VEXAS syndrome, thu…

Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis.

2019

Introduction: The advent of biologic agents has revolutionized therapeutic approaches in systemic juvenile idiopatic arthritis (sJIA) as their introduction has been shown to modify disease course and improve overall outcomes, particularly when initiated early. Few studies have reported the drug retention rate (DRR) of biologic drugs in JIA, and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on sJIA. Objectives: The primary aim of the study was to examine the overall DRR of IL-1 blockers in sJIA patients. Secondary aims of our study were to: (i) explore the influence of biologic line of treatment, adverse events (AEs), type of anti-IL-1 agent and the conc…

Additional file 2 of Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during S…

2021

Additional file 2: Appendix 2. Clinical comparison between Kawasaki Disease patients seen during SARS-CoV-2 epidemic and a Historical Cohort of Kawasaki Disease Patients.

A national cohort study on pediatric Behçet's disease: Cross-sectional data from an Italian registry

2017

Abstract Background Behçet’s disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about 25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD. Methods We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behçet’s Disease. …

Additional file 2 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 2 figure. Hierarchy of MedDra clinically-validated international medical terminology.

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry

2021

Contains fulltext : 231528.pdf (Publisher’s version ) (Closed access) BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classifica…

Drug survival of anakinra and canakinumab in monogenic autoinflammatory diseases: observational study from the International AIDA Registry

2021

Abstract Objectives To investigate survival of IL-1 inhibitors in monogenic autoinflammatory disorders (mAID) through drug retention rate (DRR) and identify potential predictive factors of drug survival from a real-life perspective. Patients and methods Multicentre retrospective study analysing patients affected by the most common mAID treated with anakinra or canakinumab. Survival curves were analysed with the Kaplan-Meier method. Statistical analysis included a Cox-proportional hazard model to detect factors responsible for drug discontinuation. Results Seventy-eight patients for a total of 102 treatment regimens were enrolled. The mean treatment duration was 29.59 months. The estimated D…

Development and implementation of the AIDA international registry for patients with Schnitzler's syndrome.

2022

ObjectiveThe present paper describes the design, development, and implementation of the AutoInflammatory Disease Alliance (AIDA) International Registry specifically dedicated to patients with Schnitzler's syndrome.MethodsThis is a clinical physician-driven, population- and electronic-based registry implemented for the retrospective and prospective collection of real-life data from patients with Schnitzler's syndrome; the registry is based on the Research Electronic Data Capture (REDCap) tool, which is designed to collect standardized information for clinical research, and has been realized to change over time according to future scientific acquisitions and potentially communicate with other…

Additional file 2 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 2 figure. Hierarchy of MedDra clinically-validated international medical terminology.

The AutoInflammatory Diseases Alliance Registry of monogenic autoinflammatory diseases

2022

ObjectiveThe present manuscript aims to describe an international, electronic-based, user-friendly and interoperable patient registry for monogenic autoinflammatory diseases (mAIDs), developed in the contest of the Autoinflammatory Diseases Alliance (AIDA) Network.MethodsThis is an electronic platform, based on the Research Electronic Data Capture (REDCap) tool, used for real-world data collection of demographics, clinical, laboratory, instrumental and socioeconomic data of mAIDs patients. The instrument has flexibility, may change over time based on new scientific acquisitions, and communicate potentially with other similar registries; security, data quality and data governance are corner …

Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

2017

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwi…

2016

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA wa…

Additional file 1 of Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during S…

2021

Additional file 1: Appendix 1.

IL-1 BLOCKADE IN PEDIATRIC RECURRENT PERICARDITIS: A MULTICENTRIC RETROSPECTIVE STUDY ON THE ITALIAN COHORT

2019

Background: Acute pericarditis is an inflammatory condition causing the occurrence of pericardial effusion. In a third of patients, the disease is recurrent. Most of the cases are idiopathic or occur after a pericardial procedure. First line treatment of idiopathic pericarditis consists in NSAIDs and colchicine; glucocorticoids represent the second line treatment in resistant or intolerant cases. The use of different biologics and immunosoppressant has been reported, with variable responses. A recent clinical trial has enlightened the effectiveness of anakinra in patients with colchicine-resistant recurrent pericarditis. Objectives: To describe the clinical characteristics and response to t…

Additional file 1 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 1 figure. Flowchart of the process.

Role of Colchicine Treatment in Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): Real-Life Data from the AIDA Network

2020

Objective. To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. Methods. Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. Results. 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in …

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor—Associated Periodic Syndrome (TRAPS): A S…

2020

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients’ data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p<0.05…

Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept

2016

Background: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). Methods: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three…

Transitional care of young people with juvenile idiopathic arthritis in Italy: results of a Delphi consensus survey

2018

OBJECTIVES: To present the results of a Delphi consensus survey among Italian paediatric and adult rheumatologists on transitional care (TC) of young people (YP) with juvenile idiopathic arthritis (JIA). METHODS: A taskforce of 27 paediatric and adult rheumatologists evaluated the applicability of the 2016 EULAR/PReS recommendations for TC to the Italian rheumatology practice and healthcare system and formulated additional country-specific statements aimed to increase their suitability. After a two-round discussion, applicability of EULAR/PReS recommendations and agreement with newly-proposed statements were voted on a 0-10 scale (where 0 = no applicability/agreement and 10 = total applicab…

Additional file 4 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 4 Table 2. Concomitant medications administered at the time of “confirmed OI”. Bio: biologic, mtx: methotrexate; ste: systemic steroids; sDMARDs: synthetic disease modifying antirheumatic drugs; *sDMARDs are intendend other than MTX.

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Ad…

2022

ObjectiveAim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome.MethodsThis is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. Th…

Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated perio…

2015

Abstract TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4+CD25− and regulatory CD4+CD25+ T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular le…

Musculoskeletal manifestations in children with Behçet's syndrome: data from the AIDA Network Behçet's Syndrome Registry

2023

AbstractThis study aims to describe musculoskeletal manifestations (MSM) in children with Behçet’s syndrome (BS), their association with other disease manifestations, response to therapy, and long-term prognosis. Data were retrieved from the AIDA Network Behçet’s Syndrome Registry. Out of a total of 141 patients with juvenile BS, 37 had MSM at disease onset (26.2%). The median age at onset was 10.0 years (IQR 7.7). The median follow-up duration was 21.8 years (IQR 23.3). Recurrent oral (100%) and genital ulcers (67.6%) and pseudofolliculitis (56.8%) were the most common symptoms associated with MSM. At disease onset, 31 subjects had arthritis (83.8%), 33 arthralgia (89.2%), and 14 myalgia (…

Persistence of disease flares is associated with an inadequate colchicine dose in familial Mediterranean fever: A national multicenter longitudinal s…

2021

Familial Mediterranean fever (FMF) is characterized by self limited episodes of fever and polyserositis.1 MEFV gene en codes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maxi mally tolerated dose for at least 6 months.4 A similar definition was confirmed by a recent consensus among experts.5 In the present na…

Development and Implementation of the AIDA International Registry for Patients With Undifferentiated Systemic AutoInflammatory Diseases

2022

ObjectiveThis paper points out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients affected by Undifferentiated Systemic AutoInflammatory Diseases (USAIDs).MethodsThis is an electronic registry employed for real-world data collection about demographics, clinical, laboratory, instrumental and socioeconomic data of USAIDs patients. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is designed to obtain standardized information for real-life research. The instrument is endowed with flexibility, and it could change over time according to the scientific acquisitions an…

Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.

2018

BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution…

Additional file 1 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 1 figure. Flowchart of the process.

Additional file 4 of Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during S…

2021

Additional file 4: Appendix 4. Clinical comparison between Kawasaki Disease patients seen during SARS-CoV-2 in high epidemic regions (Piedmont and Lombardy) and Kawasaki Disease Patients in low epidemic regions.

Additional file 3 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 3 Table 1. Complete table with the frequency of the 682 infections adjudicated by the SAC. Infections were reported after evaluation of the cases available in Pharmachild compared to the pathogens/presentations in the provisional list approved by the Safety Adjudication Committee (SAC). Data are presented as per the MedDRA High Level Term (HLT) and Preferred Term (PT) sorted by frequencies in descending order (HLT and then PT). *For definition see Step 5.

Additional file 5 of Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during S…

2021

Additional file 5: Appendix 5. Comparison of laboratory tests between Kawasaki Disease patients seen during SARS-CoV-2 in high epidemic regions (Piedmont and Lombardy) and Kawasaki Disease Patients in low epidemic regions.

Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease

2021

AbstractAim of these revised recommendations for the general management of Kawasaki disease is to encourage its prompter recognition and warrant the most appropriate therapy, based on ascertained scientific data, raising awareness of the complications related to misdiagnosis or delayed treatment. A set of 20 synthetic operative statements is herein provided, including the definition of Kawasaki disease, its protean presentations, clinical course and seminal treatment modalities of all disease phases. The application of these recommendations should improve prognosis of Kawasaki disease and prevent the progression to permanent vascular abnormalities, thereby diminishing morbidity and mortalit…

Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome-Therapeutic Outcome and Predictors of Response:…

2021

Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response.Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers.Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbation…

Anakinra drug retention rate and predictive factors of drug survival in systemic juvenile idiopathic arthritis and adult onset Still’s disease.

2019

Introduction: Only a few studies have reported the long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult onset Still’s disease (AOSD). We herein describe Anakinra (ANA) effectiveness expressed in terms of drug retention rate (DRR) and evaluate predictive factors of drug survival in sJIA and ASOD patients. Objectives: Examine the overall DRR of ANA in sJIA and AOSD patients. Explore the influence of biologic line of treatment, and the concomitant use of disease modifying anti-rheumatic drugs (cDMARDs) on DRR in the whole sample and stratified according to the disease thereafter; find eventual predictive factors associated with events l…

Additional file 4 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 4 Table 2. Concomitant medications administered at the time of “confirmed OI”. Bio: biologic, mtx: methotrexate; ste: systemic steroids; sDMARDs: synthetic disease modifying antirheumatic drugs; *sDMARDs are intendend other than MTX.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade

2022

Objective: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. Study design: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. Results: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.…

Case Report: The JAK-Inhibitor Ruxolitinib Use in Aicardi-Goutieres Syndrome Due to ADAR1 Mutation

2021

Type I Interferonopathies comprise inherited inflammatory diseases associated with perturbation of the type I IFN response. Use of Janus kinase (JAK) inhibitors has been recently reported as possible tools for treating some of those rare diseases. We describe herein the clinical picture and treatment response to the JAK-inhibitor ruxolitinib in a 5-year-old girl affected by Aicardi-Goutières Syndrome type 6 (AGS6) due to ADAR1 mutation. The girl's interferon score (IS) was compared with that of her older brother, suffering from the same disorder, who was not treated. We observed a limited, but distinct neurological improvement (Gross Motor Function and Griffiths Mental Development Scales). …

Additional file 3 of Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during S…

2021

Additional file 3: Appendix 3. Laboratory comparison between Kawasaki Disease patients seen during SARS-CoV-2 epidemic and a Historical Cohort of Kawasaki Disease Patients.

Additional file 3 of Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adj…

2020

Additional file 3 Table 1. Complete table with the frequency of the 682 infections adjudicated by the SAC. Infections were reported after evaluation of the cases available in Pharmachild compared to the pathogens/presentations in the provisional list approved by the Safety Adjudication Committee (SAC). Data are presented as per the MedDRA High Level Term (HLT) and Preferred Term (PT) sorted by frequencies in descending order (HLT and then PT). *For definition see Step 5.