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Objective The objective of this study was to use real-world data to evaluate the effectiveness and safety of canakinumab in Italian patients with systemic JIA (sJIA). Methods A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, and 6 and 12 months after starting canakinumab. The primary outcome measure of effectiveness was clinically inactive disease (CID) off glucocorticoids (GCs) treatment at 6 months. Results A total of 80 children from 15 Italian centres were analysed. Of the 12 patients who started canakinumab in CID while receiving anakinra, all maintained CID. Of the 68 with active disease at baseline, 57.4% achieved CID off GCs at 6 months and 63.8% at 12 months. In univariate analysis, the variables significantly related to non-response were number of active joints (NAJs) ≥5, history of macrophage activation syndrome (MAS) and disease duration. Multivariate analysis confirmed the association between non-response and NAJs ≥5 [odds ratio (OR) 6.37 (95% CI: 1.69, 24.02), P = 0.006] and between non-response and history of MAS [OR 3.53 (95% CI: 1.06, 11.70), P = 0.039]. No serious adverse events were recorded in this series. There were two cases of MAS during canakinumab, leading to a rate of 2.9 episodes per 100 patient years. Conclusion We have confirmed, using real-world data, the efficacy of canakinumab in sJIA in a multicentric cohort. History of MAS and higher NAJ were associated with lower probability of achieving CID.

Summary 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, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2–4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89–408·12]), followed by weight loss (59·88 [6·34–565·53]), thrombocytopenia (12·67 [2·40–66·92]), monoarticular involvement (11·30 [4·09–31·19]), hip involvement (3·30 [1·13–9·61]), and male sex (2·40 [1·03–5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01–0·20]), joint swelling (0·03 [0·01–0·09]), and involvement of the small hand joints (0·02 [0–1·05]). Interpretation Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. Funding Associazione Lorenzo Risolo.

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 national multicentric longitudinal study, we analyze the impact of colchicine treatment on disease activity and quality of life in real life in pediatric and adult patients with FMF.

Objective To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). Study design International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. Results Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. Conclusions The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.

Recent reports have described in the pediatric population a new type of hyperinflammatory response manifested following contact with SARS-CoV-2, with some of the clinical features attributable to Kawasaki disease (KD). The purpose of this commentary is to remark on a possible recent association between SARS-CoV-2 and KD. Although today little is known about the etiology of KD, the most accepted hypothesis is that of a probable viral etiology, therefore, even the SARS-CoV-2 virus could trigger, in genetically predisposed subjects, an exaggerated inflammatory response that is clinically evident like the one described in KD.

Background During the outbreak of COVID‐19 many pernio‐like lesions have been increasingly reported. The aim of the study is to describe our management of these skin manifestations and to evaluate a possible correlation to SARS‐CoV‐2 infection. Methods All patients underwent clinical and laboratory tests to detect a possible underlying connective disease and also to specific SARS‐CoV‐2 investigations such as oropharyngeal swab and IgG‐IgM serology. Results Nine patients aged between five and fifteen years old were evaluated. Skin lesions observed were purplish, erythematous and oedematous, in some cases painful and itchy. Six out of nine had respiratory and systemic symptoms (cough, nasal congestion, chills, fever, asthenia) that preceded cutaneous findings of approximately two weeks. Concerning blood exams, three out of nine had D‐dimer weakly increased, four had ANA positivity: two with a title 1:160, one with 1:320 and one with 1:5120 and a speckled pattern. The latter patient had also ENA SS‐A positive and RF positivity, confirmed at a second check, so as to allow us to make a diagnosis of connective tissue disease. Four out of nine had aPL positivity (IgM). Reactants acute phase were all negative. Oropharyngeal swabs and serology tests for SARS‐CoV‐2 was negative (borderline in one patient for IgM). No treatment was needed. Conclusions Even if we do not have enough data to prove it, we hypothesize a correlation between pernio‐like lesions and SARS‐CoV‐2 infection for an increased number of these lesions described during the pandemic and also because such manifestations appeared when temperatures were mild and patients were at home in isolation for the lockdown. Many questions remain open about interaction host‐virus. This article is protected by copyright. All rights reserved.

Made available in DSpace on 2021-06-25T10:38:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01 Healthway Objective. To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. Methods. The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. Results. A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. Conclusion. The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively. UOC Clinica Pediatrica e Reumatologia IRCCS Istituto Giannina Gaslini Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili (DiNOGMI) Università degli Studi di Genova Dipartimento di Epidemiologia e Biostatistica IRCCS Istituto Giannina Gaslini Faculty of Medicine Ain Shams University Pediatric Rheumatology Division Institute of Child Health Section of Pediatric Rheumatology SRCC Children's Hospital Rheumatology Division Pediatric Department Faculty of Medicine Ramathibodi Hospital Mahidol University Pediatric Rheumatology Clinic R G Kar Medical College Division of Rheumatology IRCCS Ospedale Pediatrico Bambino Gesù Division of Pediatric Rheumatology Institute of Child Health Sir Ganga Ram Hospital Faculty of Medicine Benha University Faculty of Medicine Alexandria University Faculty of Medicine Tanta University Faculty of Medicine Cairo University Pediatric Rheumatology Division Adolescent Health Care Unit Universidade do Estado do Rio de Janeiro Department of Internal Medicine Universidade Federal do Rio de Janeiro Servicio de Inmunología y Reumatología Hospital de Pediatría Garrahan Department of Clinical Sciences and Community Health University of Milan Division of Rheumatology University Hospital Meyer Rheumatology Division National Medical Research Center of Children's Health Sechenov First Moscow State Medical University Department of Immunology Rheumatology and Allergy Queen Rania Children's Hospital Saint-Petersburg State Pediatric Medical University UOC Pediatria a Media Intensità di Cure Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Rheumatology Department Faculty of Medicine Suez Canal University Department of Pediatrics King Faisal Specialist Hospital and Research Center Dipartimento Promise G. D'Alessandro Università degli Studi di Palermo Pediatric Department Hospital das Clínicas Botucatu Medicine University UNESP UOC Pediatria Servizio di Immuno-Reumatologia Pediatrica Azienda Ospedaliera Universitaria Gaetano Martino Messina UO Nefrologia e Reumatologia Pediatrica Azienda Ospedaliera Universitaria Gaetano Martino Department of Pediatrics School of Medicine Institute of Medical Pharmaceutical and Health Sciences Kanazawa University Pediatric Unit Ospedale Vito Fazzi Pediatric Unit AON SS Antonio e Biagio e Cesare Arrigo Children's Hospital Pediatric Department Hospital das Clínicas Botucatu Medicine University UNESP

Background Since ancient times, scurvy has been considered one of the most fearsome nutritional deficiency diseases. In modern developed countries, this condition has become very rare and is only occasionally encountered, especially in the pediatric population. Underlying medical conditions, such as neuropsychiatric disorders, anorexia nervosa, celiac disease, Crohn disease, hemodialysis, and severe allergies to food products may enhance the risk of developing scurvy. Case presentation We report the case of an otherwise healthy 3-year-old white boy who developed scurvy due to a selective restrictive diet derived from his refusal to try new food. He presented to our clinic with asthenia and refusal to walk. During hospitalization he developed severe anemia and hematochezia. A diagnosis of scurvy was assessed on the basis of nutritional history, clinical features, radiographic findings, and laboratory findings. Supplementation of ascorbic acid enabled a prompt resolution of symptoms. Conclusions Scurvy is caused by vitamin C deficiency. Cutaneous bleeding, mucosal bleeding, and anemia represent typical manifestations of the disease. These symptoms are directly connected to ascorbic acid involvement in collagen biosynthesis. Some radiographic findings can be useful for the diagnosis. Treatment aims to normalize serum levels of vitamin C in order to counteract the deprivation symptoms. The present case report demonstrates that scurvy may sporadically occur in pediatric patients, even in individuals with no predisposing medical conditions and/or potential risk factors.

Chronic inflammation represents the cornerstone of the raised cardiovascular (CV) risk in patients with inflammatory rheumatic diseases (IRD). Standardized mortality ratios are increased in these patients compared to the general population, which can be explained by premature mortality associated with early atherosclerotic events. Thus, IRD patients need appropriate CV risk management in view of this CV disease (CVD) burden. Currently, optimal CV risk management is still lacking in usual care, and early diagnosis of silent and subclinical CVD involvement is mandatory to improve the long-term prognosis of those patients. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. CV imaging provides valuable information as a reliable diagnostic tool. Currently, different techniques are employed to evaluate CV risk, including transthoracic or trans-esophageal echocardiography, magnetic resonance imaging, or computed tomography, to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. All the above methods are reliable in investigating CV involvement, but more recently, Speckle Tracking Echocardiography (STE) has been suggested to be diagnostically more accurate. In recent years, the role of left ventricular ejection fraction (LVEF) as the gold standard parameter for the evaluation of systolic function has been debated, and many efforts have been focused on the clinical validation of new non-invasive tools for the study of myocardial contractility as well as to characterize the subclinical alterations of the myocardial function. Improvement in the accuracy of STE has resulted in a large amount of research showing the ability of STE to overcome LVEF limitations in the majority of primary and secondary heart diseases. This review summarizes the additional value that STE measurement can provide in the setting of IRD, with a focus in the different clinical stages.

ᅟ Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto’s thyroiditis (HT). According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism. In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals. The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory. Conclusions 1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.

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 concomitant use of conventional disease modifying anti-rheumatic drugs (cDMARDs) on DRR; (ii) find eventual predictive factors associated with events leading to drug discontinuation. The corticosteroid sparing effect and the impact of disease duration and treatment delay on survival constituted ancillary aims. Methods: sJIA patients – diagnosed according to the revised International League of Association for Rheumatology (ILAR) criteria – treated with anakinra (ANA) and canakinumab (CAN) were enrolled in 15 Italian tertiary referral centers. Demographic, clinical and therapeutic data collected from medical records were retrospectively collected and statistically analyzed. Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to AEs occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341–8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186–7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002). Conclusion: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Italian language.The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents.The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity).A total of 1296 JIA patients (7.2% systemic, 59.5% oligoarticular, 21.4% RF negative polyarthritis, 11.9% other categories) and 100 healthy children, were enrolled in 18 centres. The JAMAR components discriminated well healthy subjects from JIA patients except for the Health Related Quality of Life (HRQoL) Psychosocial Health (PsH) subscales. All JAMAR components revealed good psychometric performances.In conclusion, the Italian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Background Macrophage activation syndrome (MAS) is a severe complication of rheumatologic conditions, mainly systemic juvenile idiopathic arthritis (sJIA), and is classified as a secondary form of hemophagocytic lymphohistiocytosis (HLH). Thrombotic microangiopathy (TMA) is a heterogeneous group of potentially fatal diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ injury. The association between TMA and HLH has been described only in single reports in renal transplant recipients1 and in two cases of virus-induced HLH2. TMA associated with MAS has never been reported so far Objectives To present the preliminary data from a multinational cohort of pediatric patients with MAS and TMA Methods The clinical charts of patients with MAS were retrospectively reviewed to identify the instances that were associated with TMA. Demographic, clinical and laboratory features at MAS and TMA onset, therapeutic interventions and outcome were collected. Results A total of 14 patients, 71.4% females, with MAS and TMA were collected. An underlying rheumatologic disease was reported in 9/14 (8 sJIA or sJIA-like illness and 1 systemic lupus erythematosus). The median age at MAS onset was 8.6 years. In 5 patients MAS and TMA occurred simultaneously, whereas in 4 TMA preceded and in 5 followed MAS. The main features at MAS and TMA onset are presented in Table. Low complement levels and reduced ADAMTS13 activity were observed in 75% and 43% of patients respectively. For MAS management, 85.7% of patients received high-dose corticosteroids and 71.4% cyclosporine; in 5 cases anakinra was added. TMA episodes were treated with plasma-exchange in 57.1% of patients; 7 patients were given biologics (1 rituximab and 6 eculizumab) with good results. Admission to the Intensive Care Unit was required in 85.7% of cases. All patients survived. Conclusion The association of MAS and TMA is a life-threatening condition, likely under-recognized. Clues to suspect TMA in a patient with MAS are the increase in LDH and decrease in platelet count out of proportion of other laboratory abnormalities, the drop in haptoglobin level, the finding of schistocytes in blood smear and the new onset of hematuria. Biologics, particularly rituximab and eculizumab, may offer an adjunctive therapeutic option for refractory cases. References [1] Esmaili H, et al. An update on renal involvement in hemophagocytic syndrome. J Nephropathol 2016; 2Fraga-Rodriguez GM, et al. Eculizumab in a child with atypical haemolytic uraemic syndrome and haemophagocytic lymphohistiocytosis triggered by cytomegalovirus infection. BMJ Case Rep2017. Disclosure of Interests Francesca Minoia: None declared, Jessica Tibaldi: None declared, Valentina Muratore: None declared, Romina Gallizzi: None declared, Claudia Bracaglia: None declared, Alessia Arduini: None declared, Elif Comak: None declared, Olga Vougiouka: None declared, Ralf Trauzeddel : None declared, Giovanni Filocamo: None declared, Concetta Micalizzi: None declared, Angelo Ravelli Grant/research support from: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Consultant for: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Speakers bureau: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche

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 74.3%, 62.9%, 49.4%, and 49.4%, respectively, without any significant differences between sJIA and AOSD patients (p = 0.164), and between patients treated in monotherapy compared with the subgroup coadministered with conventional diseasemodifying antirheumatic drugs (cDMARDs) (p = 0.473). On the other hand, a significant difference in DRR was found between biologic-naïve patients and those previously treated with biotechnologic drugs (p = 0.009), which persisted even after adjustment for pathology (p = 0.013). In the regression analysis, patients experiencing adverse events (AEs) {hazards ratio (HR) = 3.029 [confidence interval (CI) 1.750–5.242], p < 0.0001} and those previously treated with other biologic agents [HR = 1.818 (CI 1.007–3.282), p = 0.047] were associated with a higher HR of ANA discontinuation. The median treatment delay was significantly higher among patients discontinuing ANA (p < 0.0001). Significant corticosteroid-sparing (p = 0.033) and cDMARD-sparing effects (p < 0.0001) were also recorded. Less than one-third of our cohort developed AEs, and 85% were deemed mild in nature, with 70% of them involving the skin. Conclusions: Our findings display an overall excellent DRR of ANA on the long run for both sJIA and AOSD, that may be further optimized by closely monitoring patient’s safety issues and employing this IL-1 inhibitor as a first-line biologic as early as possible. Moreover, ANA allowed a significant drug-sparing effect and showed an overall good safety profile.

Made available in DSpace on 2019-10-05T16:54:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-04-01 IRCCS Istituto Giannina Gaslini Background To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status. Methods In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis. Findings Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33.0%] of 379 patients) and enthesitis-related arthritis (113 [29.8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56.7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31.5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19.1%] of 845 patients) and southern Europe (450 [18.8%] of 2400) and lowest in Latin America (54 [6.4%] of 849), Africa and Middle East (71 [5.9%] of 1209), and southeast Asia (19 [5.0%] of 379). Median age at disease onset was lower in southern Europe (3.5 years, IQR 1.9-7.3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. Interpretation Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lowerresource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Univ Genoa, Ist Giannina Gaslini, IRCCS, Clin Paediat & Rheumatol, Genoa, Italy Univ Genoa, Ist Giannina Gaslini, IRCCS, Epidemiol & Biostat Serv, Genoa, Italy Univ Genoa, Ist Giannina Gaslini, IRCCS, Sci Directory, Genoa, Italy Univ Genoa, PRINTO, IRCCS, Ist Giannina Gaslini, Genoa, Italy Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet & Maternal, Genoa, Italy Wilhelmina Childrens Hosp, Dept Pediat Immunol & Rheumatol, Utrecht, Netherlands Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India Univ Hosp 12 Octubre, Dept Pediat Rheumatol, Madrid, Spain Alfaisal Univ, Dept Pediat Rheumatol, King Faisal Specialist Hosp, Riyadh, Saudi Arabia Alfaisal Univ, Res Ctr, Riyadh, Saudi Arabia Western Univ Childrens Hosp, Hlth Sci Ctr, London, ON, Canada Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway Oslo Univ Hosp, Med Fac, Oslo, Norway Univ Oslo, Oslo, Norway Oslo Univ Hosp, Norwegian Natl Advisory Unit Rheumat Dis Children, Oslo, Norway Univ Hosp Munster, Dept Pediat Rheumatol & Immunol, Munster, Germany Hosp Sor Maria Ludovica, Rheumatol Serv, La Plata, Buenos Aires, Argentina Bucharest Emergency Hosp, Cluj Napoca, Romania Childrens Emergency Hosp, Cluj Napoca, Romania Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA Alberta Childrens Prov Gen Hosp, Div Pediat Rheumatol, Dept Pediat, Calgary, AB, Canada Sofiamed, Pediat Dept, Sofia, Bulgaria Rigshosp, Juliane Marie Ctr, Paediat Rheumatol Unit, Copenhagen, Denmark Natl Inst Rheumatism & Physiotherapy, Clin Immunol Adult & Paediat Rheumatol Dept, Budapest, Hungary Univ Latvia, Pediat Dept, Riga, Latvia Univ Latvia, Univ Childrens Hosp, Riga, Latvia Univ Estadual Paulista, Botucatu Fac Med, Botucatu, SP, Brazil Shariati Hosp, Rheumatol Res Ctr, Dept Pediat & Rheumatol, Tehran, Iran Inst Rheumatol Belgrade, Div Pediat Rheumatol, Belgrade, Serbia Thessaloniki Univ, Dept Pediat 1, Hippokrat Gen Hosp, Sch Med, Thessaloniki, Greece Univ Estadual Paulista, Botucatu Fac Med, Botucatu, SP, Brazil

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls, ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p &lt, 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p &lt, 0.01), and E/A ratio (r: −0.487, p &lt, 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p &lt, 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p &lt, 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc, endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.

Background:Measurement of disease activity level is of pivotal importance in the care of patients with juvenile idiopathic arthritis (JIA). According to the most recent requirements, both, parent’s and children’s perception should be taken into account while evaluating the disease course and assessing effectiveness of therapy. Therefore, a new disease activity evaluation tool, based only on parent assessment of the outcome, is under development and named Parent Juvenile Arthritis Disease Activity Score (parJADAS) [1].Objectives:The aim of this study is to develop the parJADAS cut-off values of moderate disease activity (MDA) and high disease activity (HDA) in JIA patients.Methods:The parJADAS (score range 0-40) is the sum of 4 values: 1) parent’s assessment of disease activity on a 21-numbered circle 0-10 VAS; 2) assessment of pain intensity on a 21-numbered circle 0-10 VAS; 3) proxy assessment of joint disease up to a maximum of 10 joints; 4) assessment of morning stiffness (MS) on a Likert scale, ranging from no MS (0 points) to > 2 hours of MS (10 points). The study dataset is composed of 2,412 patients with JIA, seen in 3389 visits with parJADAS available, enrolled in the the multinational registry PharmaChild, assessing the long-term safety of treatment of children with JIA. At each visit, subjects were subjectively rated as being in inactive disease, low disease activity, MDA, or HDA by the attending physician. For each patient, only one visit per disease state was retained.To identify the cut-offs the following methods were implemented: 1) Mapping: the 25thpercentile value of the parJADAS in patients having MDA or HDA, respectively, was calculated; 2) Youden Index: Youden Index (J) identifies the maximum potential effectiveness of the biomarker through the receiver operating characteristic (ROC) curve analysis; 3) Max agreement: The analysis of agreement was based on kappa statistics, which assesses the agreement beyond chance between 2 dichotomous ratings. The first rating was obtained using all possible parJADAS values as hypothetical test criteria; to obtain the second rating, the categorical ratings of each attending physician were dichotomized and were coded as 0 or 1.Results:Preliminary cut-off values for parJADAS with sensitivity and specificity are presented in the table.25th centileYouden IndexKappaMeanSensitivitySpecificityAUCMDA659773.482.00.853HDA14.81118.51571.287.60.892Conclusion:Tentative cut-off values for classifying the states of MDA and HAD using parJADAS were calculated. The obtained values will be tested in the validation analysis. Once validated the cut-offs are ideally suited to identify subjects at risk of disease flare when remotely monitored with the parJADAS.References:[1]Ridella F., et al. Ann Rheum Dis, volume 78, supplement 2, year 2019, page A1434.Acknowledgments:We wish to thank all researchers and patients participating in the PharmaChild registryDisclosure of Interests:Ilia Avrusin: None declared, Roberta Naddei: None declared, Francesca Ridella: None declared, Giedre Januskeviciute: None declared, Mikhail Kostik: None declared, Ben Whitehead: None declared, Romina Gallizzi: None declared, Elzbieta Smolewska: None declared, Serena Pastore: None declared, Philip Hashkes: None declared, Joost F. Swart: None declared, Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Angelo Ravelli: None declared, Alessandro Consolaro Grant/research support from: Pfizer Inc., AlfaSigma, Speakers bureau: AbbVie

Aim of this commentary is to analyze the relationships between genotypic bases and phenotypic expression of congenital “multiple pituitary hormone deficiency” (MPHD) syndrome and to indicate some reliable criteria for selecting the patients who should undergo genetic analyses in order to clarify the etiology of their disorder. On the basis of the most recent reports on this topic, it is possible to infer that: 1) in only few patients with congenital MPHD it is possible to detect a causative gene mutation; 2) therefore, it is fundamental to define some criteria for selecting the patients who should undergo genetic analyses; 3) such inclusion criteria should be based on the overall evaluation of hormonal clinical and neuroradiological phenotype; 4) it is crucial to consider whether the cases are sporadic or familial, since the probability of finding a causative gene mutation is distinctly higher in familial cases; 5) for PROP1 gene it is also important to consider the geographical origin of the patients, because this mutation is much more frequent in some ethnic groups.

Aim of this commentary is to report the main peculiarities that have been found to characterize the phenotypic expression of autoimmune thyroid diseases (AITDs) in children with Down’s syndrome (DS). According to recent reports, DS children are, per se, more exposed to the risk of both Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), irrespective of other concomitant risk factors, such as female gender and family antecedents for AITDs. In the context of extra-thyroidal autoimmune disorders, the ones that preferentially aggregate with AITDs in DS children are alopecia areata and vitiligo. Another peculiar aspect, in DS children, is that HT presents with a more severe biochemical picture, which furtherly deteriorates over time. By contrast, GD does not demonstrate a more severe clinical and biochemical picture with respect to that generally observed in patients without DS. Finally, DS children might be at higher risk of progressing from HT toward GD over time.

IntroductionAutoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting.MethodsThe ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an ‘observer-nested-within-subject’ design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach’s alpha.ResultsThe ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.ConclusionThe ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.

Aim of this commentary is to analyze the current views about the phenotypic features of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) in Turner syndrome (TS) girls, in terms of epidemiology, clinical and biochemical presentation, long-term course and metamorphic autoimmunity evolution. In TS GD course is not atypical, whereas HT course is characterized by both a mild presenting picture and a severe long-term evolution of thyroid function tests. Furthermore, TS girls seem to have an increased risk of switching over time from HT to GD. On the light of these findings, it may be concluded that TS girls with HT need a careful monitoring of thyroid status over time. Conclusions: 1) In children the association with TS is able to condition a peculiar phenotypic expression of HT in terms of epidemiology, presentation course and long-term metamorphic autoimmunity; 2) by contrast, children with TS do not exhibit an atypical clinical and biochemical course of GD, but only a significantly higher prevalence of this disease.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Italian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, test–retest reliability, and construct validity (convergent and discriminant validity). A total of 1296 JIA patients (7.2% systemic, 59.5% oligoarticular, 21.4% RF negative polyarthritis, 11.9% other categories) and 100 healthy children, were enrolled in 18 centres. The JAMAR components discriminated well healthy subjects from JIA patients except for the Health Related Quality of Life (HRQoL) Psychosocial Health (PsH) subscales. All JAMAR components revealed good psychometric performances. In conclusion, the Italian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Objective.To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey.Methods.International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course.Results.A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide.Conclusion.The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Behçet’s disease (BD) is a multisystem disorder of unknown aetiology, characterized by recurrent oral ulcers, genital ulcers, uveitis, skin lesions, and pathergy. Gastrointestinal disease outside the oral cavity is well recognized and usually takes the form of small intestinal ulcers, with the most significant lesions frequently occurring in the ileocaecal region. Symptoms usually include nausea, vomiting, colicky abdominal pain, and change in bowel habit and it is not unusual that patients may present late, with life-threatening complications requiring surgery. Diagnosis has been hindered for many years by limitations in imaging the small bowel and it is usually achieved by means of endoscopy and CT of the abdomen. Magnetic resonance enterography (MRE) is a relatively new technique, which has a high diagnostic rate in patients with Crohn’s disease (CD). Although many similarities between CD and intestinal BD have already been described in literature, the role of MRE in the evaluation of intestinal BD has never been defined up to now. We report a case of a 12-year-old female patient with diagnosis of BD who presented at our institution for recurrent colicky abdominal pain and diarrhoea. The patient underwent MRE that demonstrated the gastrointestinal involvement.

Background Behcet’s disease (BD) is a chronic immune-mediated, inflammatory disorder which may affect a number of different systems (oral and genital mucosa, eyes, skin, vascular district, joints, gastrointestinal tract and nervous system). Neurological manifestations are present in 5–10%, and gastrointestinal tract involvement in 10–15% of cases. The simultaneous involvement of two systems, neurological and gastrointestinal tract, is very rare and represents the aim of our case report. Case presentation We describe a case of a 12-year-old girl with neurological (endocranial hypertension, papilledema, retinal vasculitis) and gastrointestinal tract (terminal ileum and cecum inflammation) involvement and with a history of recurrent oral aphthosis; therefore, according to both International Criteria for Behcet’s Disease (ICBD) and Paediatric Behcet’s Disease criteria (PEDBD) the diagnosis of BD was confirmed. Conclusions This case report is one of the few described in literature with simultaneous involvement of the two systems, neurological and gastrointestinal tract, in paediatric BD. The diagnosis is really difficult because there is no specific diagnostic test. We think that our clinical case should help clinicians to suspect a BD with an unusual onset.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

ObjectivesAutoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency.MethodsWe developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds.ResultsMore than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain.ConclusionsAn instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process.

Objective.To evaluate the rate of somatic NLRP3 mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS).Methods.The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the NLRP3 gene yielded negative results. Patients’ DNA were subjected to amplicon-based NLRP3 deep sequencing.Results.Low-level somatic NLRP3 mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). In vitro functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging.Conclusion.The allele frequency of somatic NLRP3 mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated.

Behcet’s disease (BD) and Crohn’s disease (CD) are chronic immune-mediated, inflammatory disorders affecting many different systems (joints, skin, eyes, gastrointestinal and biliary tracts). Both disorders have fluctuating courses and when gastrointestinal symptoms are prevalent, differential diagnosis can be difficult. BD involves the gastrointestinal tract in 10–15% of cases with localized lesions in the ileocecal region. The clinical picture is heterogeneous with various clusters of disease expression. CD is a chronic inflammatory disorder, which can affect any part of the intestinal tract, as well as extra-intestinal tissue. Factors that contribute towards the pathogenesis of both disease include the host’s genetic profile, and immune system, and environmental factors such as the gut microbiota. The aim of this manuscript is to provide a narrative review of clinical features of BD and CD, highlighting the importance of differential diagnosis and therapeutic approach, especially in the presence of gastrointestinal involvement. A comprehensive search of published literature using the Pubmed ( http://www.ncbi.nlm.nih.gov/pubmed/ ) database was carried out to identify all articles published in English from 1999 to October 2016, using 4 key terms: “Behcet Disease”, “Intestinal Behcet’s Disease”, “Crohn’s Disease” and” Inflammatory Bowel Disease”.

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. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria. Results The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn’t fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement. Conclusions Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.

Hashimoto encephalopathy is a syndrome of encephalopathy associated with elevated concentration of circulating serum anti-thyroid antibodies usually responsive to steroid therapy. We report a 13-year-old girl with Hashimoto encephalopathy and peripheral nervous system involvement. The child had experienced high-grade pyrexia, global headache and sleeplessness. After admission she had an ileus with a distended urinary bladder, hallucinations and cognitive impairment. She had reduced deep tendon reflexes and distal sensory deficiency. Anti-thyroglobulin antibodies were raised at 2121 IU/mL (normal, 0-40) and the anti-thyroperoxidase was high at 886 IU/mL (normal, 0-50). Progressive neurological and psychiatric remission was noted after i.v. methylprednisolone. Follow-up magnetic resonance imaging showed complete resolution of the foci of signal abnormality previously yielded. This case report is the first, to the best of our knowledge, to describe peripheral nervous system involvement in a child with a diagnosis of Hashimoto's encephalopathy.

Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Autoimmune Hepatitis (AIH) is a cryptogenic, chronic and progressive necroinflammatory liver disease. Common features of AIH are hypergammaglobulinemia (IgG), presence of circulating autoantibodies, histological picture of interface hepatitis and response to immunosuppressant drugs. Conventional treatment with Prednisone and Azathioprine is effective in most patients. We describe the case of a 6 years-old girl with Noonan Syndrome and Autoimmune Hepatitis type 1. Molecular analysis of PTPN11 gene showed heterozygous mutation c.923A>G (Asn308Ser) in exon 8. Though association between NS and autoimmune disorders is known, this is the second case of association between Noonan Syndrome and Autoimmune Hepatitis type 1 described in literature. In the management of NS, an accurate clinical evaluation would be recommended. When there is a clinical suspicion of autoimmune phenomena, appropriate laboratory tests should be performed with the aim of clarifying whether the immune system is involved in NS. We think that autoimmunity represents a characteristic of NS, even if the etiopathogenesis is still unknown.

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 groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. Results: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. Conclusions: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

Joubert syndrome (JBTS) is a rare autosomal recessive disorder with an underestimated prevalence due to lack of recognition of clinical signs or failure to diagnose this pathology. JBTS is clinically heterogeneous, and it is characterized by a multiple organ involvement predominantly due to the requirement for Joubert gene function in several tissues. Renal disease affects approximately 30% of patients with JBTS, presenting itself in most cases as nephronophthisis (NPHP), a structural tubulo-interstitial disorder characterized by thickened basal membrane of the tubular epithelium and progressive interstitial fibrosis, associated with cysts at the cortico-medullary junction. We propose three cases concerning three patients with JBTS having different years of illness and degrees of renal impairment, evaluating the parameters of renal function at the time of genetic diagnosis and seen after a follow-up of 7 years. We measured neutrophil gelatinase-associated lipocalin (NGAL), considered as an excellent predictor of kidney injury, to evaluate whether this biomarker might be an early biomarker for JBTS-related kidney disease. NGAL was high in all three cases, but with different levels, indicating a tubular suffering typical of this syndrome, with dissimilar severity in the analyzed subjects. NGAL could represent an early indicator of renal damage useful to start an intensive nephrologic follow-up.

Common variable immunodeficiency (CVID) is a primary immune disorder characterized by low immunoglobulin serum levels and increased susceptibility to infections. Underlying genetic causes are only known in less than 15% of patients and encompass mutations in the genes encoding for ICOS, TACI, BAFF-R, CD19, CD20, CD81 and MSH5. TACI is the most frequently mutated gene among CVID patients. We report on two pediatric Italian male siblings with hypogammaglobulinemia and recurrent respiratory and gastrointestinal infections in association with a novel compound heterozygous TACI mutation. Both patients carry the I87N/C104R mutation that has not been reported yet. This results in aberrant TACI expression and abrogates APRIL binding on EBV B cells. This study identifies a novel combined mutation in TNFRSF13B increasing the spectrum of TACI mutations associated with CVID.

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.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. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria.The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn't fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement.Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.

The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients.

Objective To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever. Methods 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients. Results Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of ‘familial Mediterranean fever (FMF)-like symptoms’ decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for ‘periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms’. Conclusions This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.

The importance of early life environmental influences on the etiology of asthma is implied by the observed geographic and temporal variation in the prevalence of the disease among children. There is evidence pointing to the role of exposure to allergen, various aspects of diet and hygiene-related factors in the etiology of asthma. There is also evidence that heritable factors influence the impact of hygiene-related exposures on the risk of having asthma. A number of important gene-environment interactions have been identified. These interactions point to the biology of environmental exposures as the involved genetic variation is suggestive of certain underlying mechanisms. Polymorphisms within genes coding for the toll-like receptor-lipopolysaccharide (TLR-LPS) signaling pathway may underlie variations in effects of hygiene-related exposures, including specifically endotoxin, on the risk of developing allergic sensitization and allergic disease. This review presents recent findings illustrating the role of gene-environment interactions in childhood asthma susceptibility.

The aim of the present study was to evaluate the long term follow-up of patients enrolled in the Italian Registry of cryopirin associated periodic sindrome (CAPS).

Mastocytosis refers to a heterogeneous group of rare disorders characterized by an abnormal accumulation of mast cells in one or more organ systems. Cutaneous mastocytosis (CM) is the most frequent form in children and is characterized by hyperpigmented macules or papules symmetrically distributed over the trunk, and less so over the limbs, neck, and scalp. Two published articles have reported on unrelated girls presenting with mastocytosis, microcephaly, hearing loss, and hypotonia. Based on the original observation, this disorder was defined as CM with short stature, conductive hearing loss, and microtia (OMIM 248910). Here we report on a girl with similar manifestations who corroborates the existence of this rare disorder. CM, microcephaly, microtia, and/or hearing loss are the minimal diagnostic criteria. All the known patients were sporadic, but parental consanguinity in the first case argues for a possible autosomal-recessive inheritance.

Inflammatory bowel diseases such as Crohn disease and ulcerative colitis are frequently clinical conditions in children. Another clinical entity, indeterminate colitis, is considered a subgroup of pediatric inflammatory bowel disease. It is generally characterized by early onset in the first years of life, and clinical behavior is rapidly progressive to pancolitis. The definition of indeterminate colitis has changed over the years, but it is usually used to identify severe colitis with overlapping features of ulcerative colitis and Crohn disease. Ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis, but increased rates of complications have been found in indeterminate colitis. Therefore, it is better to be cautious in patients with indeterminate colitis who present with severe attacks and require surgery.

Background The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients. Objectives To evaluate the outcome of etanercept (ETN) therapy in Italian children with JIA. Methods This is a multicenter, observational study that includes all children with JIA who were given ETN at Italian pediatric rheumatology centers after January 2000. Patients were classified in 2 groups: patients who were no longer taking ETN at study start (Group 1); patients who were still receiving ETN at study start (Group 2). Patients in Group 1 underwent only retrospective assessments, whereas patients in Group 2 underwent both retrospective and cross-sectional assessments. The primary outcome of the study were reasons for ETN discontinuation in patients in Group 1, and achievement of the states of inactive disease (ID), minimal disease activity (MDA) and parent- and child-acceptable symptom state (PASS, CASS) in patients in Group 2. The above states were assessed through both formal definitions and JADAS cutoffs. The secondary outcome was the evaluation of frequency and characteristics of ETN-related side effects. Results So far, the data of 1019 patients (629 in Group 1 and 390 in Group 2) have been collected. Among the 629 patients in Group 1, reasons for ETN discontinuation evaluated in 460 patients included disease remission (48.5%), lack of efficacy (26.1%), and side effects (14.8%). The results of assessment of disease state through formal definitions in 371 children of the 390 children in Group 2 who had already undergone the cross-sectional evaluation were the following: ID 39.7%, MDA 63.0%, PASS 82.4%, CASS 75.8%. The percentages of patients who reached the same disease states assessed through JADAS cutoffs were: ID 45.9%, MDA 61.6%, PASS 70.0%, CASS 66.2%. Serious adverse events were seen in 17 patients and included inflammatory bowel disease (8 pts), tuberculosis (1 pt), CMV hepatitis (1 pt), recurrent pneumoniae (1 pt), varicella complicated by bronchopneumonia (1 pt), acute pancreatitis (1pt), bacterial osteomyelitis (1 pt), bladder carcinoma (1pt), thyroid carcinoma (1 pt); 1 patient died of sepsis. Conclusions A substantial proportion of children currently receiving ETN were in the states of ID or MDA, or were satisfied with treatment outcome. Half of the patients who had been discontinued from ETN before study start had the medication stopped because of disease remission. Serious adverse events were uncommon. Disclosure of Interest None declared

A multinational collaborative effort aimed to develop a new set of criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sjia) is ongoing. The data-collection phase of the project has been recently completed

Methods MVK gene was analyzed in 950 consecutive patients with periodic fever. 40 MKD patients were identified. Spontaneous disease course was classified as follows: i) resolution (no episodes in the last 6 months), ii) improvement (reduction of more then 30% of fever episodes) iii) stationary iv) worsening (increase frequency of fever episodes or appearance of new major clinical manifestation).The Child Health Questionnaire (CHQPF 50) was used to assess the health related quality of life (HRQL). An international sample of 3315 healthy children (52.2% female), with a mean (SD) age of 11.2 (3.8) years constituted the healthy control group.