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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 a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p=0.42), between low- and high-penetrance mutations (p=0.62), and according to different dosages (p=0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. Conclusions. Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.

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.

The autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin(IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoringin vivodecay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.

Background: MIS-C is a potentially severe inflammatory syndrome associated with SARS-CoV-2 exposure. Intravenous immunoglobulin (IVIG) is considered the first-tier therapy, but it implies infusion of large fluid volumes that may worsen cardiac function.Patients and Methods: Since April 2020, we have developed a treatment protocol that avoids the infusion of IVIG as first-line therapy in the early phase of MIS-C. In this study, we retrospectively analyzed a cohort of consecutive patients treated according to this protocol between 01/04/2020 and 01/04/2021.Results: In the last year, 31 patients have been treated according to the protocol: 25 with high-dose pulse MP (10 mg/kg) and 6 with 2 mg/kg. 67.7% of the patients responded to the initial treatment, while the others needed a step-up, either with Anakinra (25.8%) or with MP dose increase (6.5%). IVIG was administered in four patients. Overall, only one patient (3.2%) needed ICU admission and inotropic support; one patient developed a small coronary artery aneurysm.Conclusions: Timely start of MP therapy and careful fluid management might improve the outcomes of MIS-C patients.

Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-κB dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.

BACKGROUND Despite efforts made to prevent the spread of multi-drug-resistant bacteria, carbapenemase-producing Enterobacteriaceae (CPE) has become one of the most dangerous threat worldwide. However, data on the epidemiology of CPE and on the correlation between CPE colonization and infection are scanty. The objectives of this study were first to describe the epidemiological characteristics of colonizations and invasive CPE infections in the pediatric population, and second, to apply the Giannella Risk Score (GRS) to the pediatric population for the assessment of the risk of invasive CPE infection in patients with already known colonization. METHODS Pediatric patients with evidence of colonization by CPE were retrospectively enrolled. For each colonized patient, the subsequent development of an infection by CPE was then assessed for a 90-day period after the first CPE isolation; GRSs were compared between patients who had developed any type of CPE infection and those without infection. RESULTS A total of 215 patients (113 males and 102 females) with at least 1 isolation of CPE during hospitalization were analyzed. Median age was 5.6 years [interquartile range (IQR), 1.89-12.2 years]. Overall, 28 CPE infections (13%) were documented: 23 blood stream infections and 5 complicated urinary tract infections. The 30-day mortality of invasive CPE infections was 34.8%. The GRS values in patients with any CPE infection were statistically higher than in noninfected patients: median GRS 9 (IQR, 4-12.5) versus 4 (IQR, 2-4), respectively; P < 0.0001. The analysis of the receiver operating characteristic curves identified a GRS cut-off value ≥8 as the best predictor of CPE infection. The likelihood ratio of the results was

Background There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group – KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients’ outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p Conclusion Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

Since April 2020, an increasing number of authors have reported a new clinical syndrome related to SARS-COV2 infection in children, characterized by rapidly progressive systemic inflammation with multiorgan dysfunction. This syndrome has been addressed with many names since its description such as Multisystem Inflammatory Syndrome in children (MIS-C), Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-ST), and SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome (SCiKH).1-3 The pathogenesis of MIS-C is still unknown, even if the positivity of a nasopharyngeal RT-PCR assay for the SARS-COV2 and/or of specific antibody testing in most patients suggests that this syndrome develops while the immune system is activated against the SARS-COV2 virus.

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype–phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.

Antimicrobial resistance is one of the most relevant threats in public health worldwide. Strategies as antimicrobial stewardship programs, aiming to preserve our antibiotic armamentarium, have been implemented since 2007 in adult and paediatric patients. We aim to describe the first experience of a paediatric antimicrobial stewardship program. We conducted a retrospective observational study in a tertiary care children's hospital. A team composed of a microbiologist, an infectious diseases physician, and a paediatrician led the project. All positive blood and cerebrospinal fluid cultures and other biological samples yielding multi-drug-resistant bacteria were collected and reviewed through a prospective-audit-with-feedback strategy. We recorded patient characteristics and worth monitoring prescribed antibiotics. The antimicrobial stewardship audit could end in intervention (step-up/step-down and broadening/narrowing) or recommendation(s). We then checked out wards staff compliance. The team performed 192 interventions out of 584 reviews, mostly suggesting discontinuation of antibiotics (in 76.0% of cases and 39.7% of running molecules). The antibiotic spectrum was more likely tapered than expanded (p < 0.0001), and we ordered more narrow-spectrum antibiotic molecules than local medical staff straightaway did (p = 0.0113). Interventions were most likely needed in case of documented infections (p < 0.0001) and in surgical patients (p = 0.0002). In 85.9% of interventions, ward teams fully agreed with our argument. This study demonstrated an antimicrobial stewardship program to be a suitable method for improving the appropriateness of antimicrobial use in hospitalized children.

On March 11th, 2020 the World Health Organization declared COVID-19 a global pandemic. The infection, transmitted by 2019 novel coronavirus (2019-nCov), was first discovered in December 2019, in Wuhan, Hubei Province, and then rapidly spread worldwide. Italy was early and severely involved, with a critical spread of the infection and a very high number of victims. Person-to-person spread mainly occurs via respiratory droplets and contact. The median incubation period is 5 days. The spectrum of respiratory symptoms may range from mild to severe, strictly depending on the age of the patient and the underlying comorbidities.In children COVID-19 related disease is less frequent and less aggressive. In Italy 1% of positive cases are under 18 years of age, and no deaths have been recorded before 29 years of age. For patients affected by rheumatic disease, despite the concerns related to the imbalance of their immune response and the effect of immunosuppressive treatments, there are still few data to understand the real consequences of this infection. Major scientific societies have issued recommendations to help rheumatologists in caring their patients. Interestingly, some of the drugs mostly used by rheumatologists appear to be promising in critical COVID-19 infected patients, where the hyperinflammation and cytokine storm seem to drive to the multiorgan failure.Pediatric rheumatologists are expected to play a supporting role in this new front ofCOVID-19 pandemic, both as general pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs.

We describe 2 children with persistent fever and profuse diarrhea who developed signs of mucocutaneous involvement (conjunctivitis, fissured lips, skin rash, erythema, and edema of the hands and feet). Blood tests revealed elevated markers of inflammation, lymphopenia, thrombocytopenia, and complement consumption. Afterward, diffuse edema with hypoalbuminemia appeared in the context of a capillary leak syndrome. In both patients, repeated nasal swabs were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but each patient had high titers of immunoglobulin G and immunoglobulin M against the SARS-CoV-2 virus. The negative PCR results in the presence of immunoglobulin M and immunoglobulin G suggested that the inflammatory response developed in the late phase of viral infection, when SARS-CoV-2 was not detectable in the upper airway. In this report, we describe patients with what we propose to name as SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome. SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome seems to be caused by a delayed response to SARS-CoV-2. It resembles Kawasaki disease complicated by macrophage activation syndrome, although it has peculiar features, such as prodromal diarrhea, capillary leak syndrome, and myocardial dysfunction. Intravenous corticosteroid treatment appears to be helpful.

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Children with the new coronavirus disease 2019 (COVID-19) have milder symptoms and a better prognosis than adult patients. Several investigations assessed type I, II, and III interferon (IFN) signatures in SARS-CoV-2 infected adults, however no data are available for pediatric patients. TRIM28 and SETDB1 regulate the transcription of multiple genes involved in the immune response as well as of human endogenous retroviruses (HERVs). Exogenous viral infections can trigger the activation of HERVs, which in turn can induce inflammatory and immune reactions. Despite the potential cross-talks between SARS-CoV-2 infection and TRIM28, SETDB1, and HERVs, information on their expressions in COVID-19 patients is lacking. We assessed, through a PCR real time Taqman amplification assay, the transcription levels of six IFN-I stimulated genes, IFN-II and three of its sensitive genes, three IFN-lIIs, as well as of TRIM28, SETDB1, pol genes of HERV-H, -K, and -W families, and of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis-associated retrovirus (MRSV) in peripheral blood from COVID-19 children and in control uninfected subjects. Higher expression levels of IFN-I and IFN-II inducible genes were observed in 36 COVID-19 children with mild or moderate disease as compared to uninfected controls, whereas their concentrations decreased in 17 children with severe disease and in 11 with multisystem inflammatory syndrome (MIS-C). Similar findings were found for the expression of TRIM-28, SETDB1, and every HERV gene. Positive correlations emerged between the transcriptional levels of type I and II IFNs, TRIM28, SETDB1, and HERVs in COVID-19 patients. IFN-III expressions were comparable in each group of subjects. This preserved induction of IFN-λs could contribute to the better control of the infection in children as compared to adults, in whom IFN-III deficiency has been reported. The upregulation of IFN-I, IFN-II, TRIM28, SETDB1, and HERVs in children with mild symptoms, their declines in severe cases or with MIS-C, and the positive correlations of their transcription in SARS-CoV-2-infected children suggest that they may play important roles in conditioning the evolution of the infection.

Background Oligoarticular juvenile idiopathic arthritis (oJIA) is the most frequent form of chronic arthritis in children; the clinical course is extremely variable. In this study we have characterized by flow cytometry synovial B and T cells subsets in patients with oJIA in order to identify any parameters that could predict a more aggressive course of disease. Methods B and T cells from synovial fluid (SF) of 39 patients with oJIA were characterized by flow cytometry. In 22 patients SF was analysed at the onset of the disease (GroupA), in 17 SF was analysed at articular relapse (Group B). All patients in Group A were followed up for at least for 2 years after SF analysis: 13 patients relapsed during the follow-up period. Results Comparison of SF from Group A and Group B demonstrated an activated phenotype in relapsed patients, with higher Switched Memory B cells (58.53 vs 36.07% of CD19+, p-value 0.004) and lower Naive B cells (8.53 vs 25.9 of CD19+, p-value 0.002) in Group B. Furthermore, patients from Group A who did not relapse showed lower percentages of synovial DNT (2.38 vs 1.50% of CD3+TCRalpha/beta+, p-value 0.025) and γδ T cells (19.1 vs 15.0% of CD3+ cells, p-value 0.004) at the onset, if compared with other Group A patients. Conclusions In oJIA relapse SF present an activated B phenotype. Patients at disease onset with DNTs

Background Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations). Aim To study the mutation spectrum in ICF syndrome. Materials and methods Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. Results We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients. Discussion The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort. Conclusion Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.

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 TMJ is involved in about 50% of JIA cases, often bilateral and asymptomatic in up to 71% of cases1. Adult patients with JIA have been shown to have, compared to healthy individuals, higher rate of dysfunction and anatomical abnormalities2. Clinical examination has been shown to have high specificity but low sensitivity in revealing TMJ inflammation3. To date MRI is the gold standard to assess TMJ involvement 4 Objectives To investigate the prevalence of TMJ involvement in young adults with JIA and young adults with non-JIA inflammatory rheumatisms. Methods Patients were recruited prospectively in 2 clinical centers. Inclusion criteria were: patients Results 19 patients were included in the JIA group and 8 patients in the non-JIA group. Patients’ demographic and disease characteristics were reported in Table 1. MRI results are collected in Table 2. There are no statistically significant differences between groups for the presence of inflammation on MRI, while damage (in particular, disk abnormalities) is more likely in JIA rather than non-JIA patients (p= 0.02). Joint effusion is more likely to be mild rather than moderate/severe in JIA patients (p = 0.04). Conclusion It was found that it is more likely to find damage on MRI in patients of both groups rather than inflammation. Both groups show the same frequency of TMJ involvement, suggesting that TMJ involvement must be sought by the adult rheumatologist as it not only affects JIA patients, but also those with adult-onset inflammatory arthropathies. References [1] Billiau AD, et al. J Rheumatol. 2007 Sep;34(9):1925–33 [2] Arvidsson LZ, et al. Radiology 2010 Jul;256(1):191–200 [3] Koos B, et al. J Rheumatol. 2014 Sep;41(9):1871–7 [4] Hemke R, et al. Eur Radiol. 2014 Feb;24(2):327–34. Disclosure of Interests None declared

Background Interferons (IFNs) seem to play an important role in the pathogenesis of juvenile dermatomyositis (JDM). Our group previously reported that expression of both type I and type II IFN related genes is increased in muscle biopsies of JDM patients and correlates with histological and clinical features of the disease. Objectives The aim of this study was to investigate expression of interferon regulated genes (IRGs), as well as serum levels of two type I and type II IFN induced chemokines (CXCL9, CXCL10) and neopterin in peripheral blood of JDM patients and to assess their correlations with clinical and laboratory findings. Methods We collected 189 blood samples from 39 JDM patients at different time points during follow-up. In 11 patients we obtained the first blood sample at time of muscle biopsy. We measured expression of type I IRGs (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1), IFNg and type II IRGs (CXCL9, CIITA, IDO1) by quantitative PCR (qPCR) and calculated a type I and type II IFN score for muscle and blood samples; serum levels of CXCL9, CXCL10 and neopterin were analyzed by ELISA. Ten healthy subjects were used as controls (HC). At each visit, the following clinical data were recorded: physician’s global assessment (PGA) of disease activity VAS (Visual Analogue Scale), cutaneous VAS, Cutaneous Assessment Tool (CAT) activity score, Childhood Myositis Assessment Score (CMAS), serum levels of creatine phosphokinase (CK, IU/l), presence of myositis specific or myositis associated antibodies (MSA/MAA), prednisone (or equivalent) dose (mg/kg/daily), ongoing immunosuppressive medications. Results Serum levels of CXCL9 where significantly correlated with muscle expression of IFNg and type II IFN score. The correlation of CXCL10 levels with muscle type I and type II IFN score was weaker. Muscle expression of CXCL9 and CXCL10 correlated with serum levels of these chemokines. Type I IFN score in blood of JDM patients was increased compared to HC and significantly correlated with PGA, cutaneous VAS, CAT activity score. Serum levels of CXCL9 and CXCL10 were significantly higher in JDM patients compared to HC. MSA positive JDM patients showed higher levels of CXCL9 and CXCL10 compared to MSA negative patients. CXCL10 levels correlated with PGA and CMAS, but not with cutaneous disease activity. CXCL9 showed no significant association with the evaluated clinical features. Neopterin levels significantly correlated with PGA, cutaneous VAS, CAT activity score and CMAS. Conclusion Our findings indicate that expression of IRGs, measured as type I IFN score, and serum levels of CXCL10 and neopterin reflect specific features of disease activity in JDM, supporting their role as valuable disease biomarkers. References [1] Moneta GM, Pires Marafon D, Marasco E, Rosina S, Verardo M, Fiorillo C, Minetti C, Bracci-Laudiero L, Ravelli A, De Benedetti F, Nicolai R. Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histological Features. Arthritis Rheumatol. 2018 Dec 15. doi: 10.1002/art.40800. Acknowledgement This work was supported by a grant of the Cure JM Foundation to Dr. Nicolai and by funding of the Ospedale Pediatrico Bambino Gesu IRCCS to Dr. De Benedetti Disclosure of Interests Rebecca Nicolai: None declared, Ivan Caiello: None declared, Lucilla Rava’: None declared, Silvia Rosina: None declared, Luisa Bracci-Laudiero: None declared, Francesco Licciardi: 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, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Gian Marco Moneta: None declared

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs. The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% (n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

Background Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. Objective To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. Methods We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. Results Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naive CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naive ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. Conclusions Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

ObjectivesTo describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs).MethodsClinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases.ResultsThis study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%).ConclusionThis study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.

Background:Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Musculoskeletal ultrasound (MSUS) is a reliable tool in the assessment of chronic inflammatory arthropathies. MSUS in JIA has demonstrated a higher sensitivity for detecting synovitis and tenosynovitis as compared to physical examination. The occurrence of subclinical synovitis (Sub-S: MSUS+/ physical examination -) seems more frequent in wrist and foot joints; the clinical significance of Sub-S in real-life practice is still debated. Methotrexate (MTX) is the most widely used first-line DMARD in JIA therapy. Weekly treatment with MTX leads to clinical remission (CR) in 50-70% of patients. After a variable period of CR (usually 6-18 months), MTX is discontinued. Relapse rate after MTX suspension ranges between 40-50%; no predictors of disease flare have been identified so far.Objectives:We designed a cohort study in order to explore if MSUS monitoring during MTX tapering was able to predict disease flare.Methods:JIA patients in CR (as defined by the JADAS score) for at least 12 months were enrolled in the study. Patients at first attempt of suspension (G1) were tapered as follows: 1 week of suspension every 3 weeks for 3 months + 1 dose every 2 weeks for 3 months; if CR persisted, MTX was stopped. Patients who had a previous flare during/after MTX tapering (G2) had a similar tapering schedule but the step with 1 MTX dose every 2 weeks lasted 6 months. All patients underwent a complete MSUS of 48 joints every 3 months; clinicians who performed physical examinations and follow-up were blinded to US findings for the entire study period.Results:18 consecutive patients were enrolled between April 2018 and September 2019; patients had prevalently oligoJIA (55.5%) and RF- polyJIA (22.2%). Patients had been treated with MTX for 24.7 months (17.7–48.3), CR had been achieved 4.2 months after MTX start; 61.1% were at their first attempt of MTX tapering (G1).Baseline MSUS:at T0 MSUS detected 9/18 patients (50.0%) with Sub-S (MSUS+). Affected sites at T0 were distributed as follows: 4 MCP joints, 9 MTP joints, 1 f-IP joints, 11 knees. No significant differences resulted in comparing demographic and baseline disease features between MSUS- and MSUS+ patients at T0.Follow-up MSUS: 14 patients (77.8%) completed the entire study protocol, 4 patients are still ongoing. 7 patients relapsed: 42.9% during tapering, 1 of them relapsed during a VZV infection and was excluded from further analysis. We considered as Tlast-MSUS the last available MSUS before relapse or final MSUS (i.e. three months after MTX withdrawal) for not-relapsed subjects.At Tlast8 patients had at least 1 Sub-S. Sub-S per patient at Tlastwere more than Sub-S at T0 (2.85 vs 0.53 p=0.03) but the presence of Sub-S was not related with disease flare (50.0 vs 44.4% p=1). MSUS found 27 Sub-S of the small joints (sMSUS): 88.9% were in the feet, they had an OMERACT grading of 1. sMSUS+ patients were older (8.7 vs 3.9, p=0.002) therefore a weight-induced sub-S not related with JIA could be presumed.Kaplan-Meier curves were analyzed comparing MSUS results at T0 and Tlast, both considering all Sub-S and excluding small feet joints (pMSUS). The best performance was achieved with MSUS at Tlastand pMSUS (figure below, p=0.11).Conclusion:•Sub-S are present in 50% of patients in clinical remission >12 months.•Sub-S in older patients interest often feet small joints; these Sub-S may be of mechanical origin and are not associated with disease flare.•Sub-S increase during MTX tapering.Further patients must be enrolled to understand if Sub-S excluding feet small joints may predict disease flare.References:[1]Amendment of the OMERACT US definitions of joints’ features in healthy children using the DOPPLER technique. Collado P et al, Pediatr Rheumatol Online J. 2018.[2]Preliminary Definitions for the Sonographic Features of Synovitis in Children. Roth J, et al; Arthritis Care Res. 2017.Disclosure of Interests:Francesco Licciardi: None declared, Marta Dellepiane: None declared, Carlotta Covizzi: None declared, Fabiana Figus: None declared, Irene Azzolin: None declared, Davide Montin Speakers bureau: Not relevant for the topic, Annamaria Iagnocco Grant/research support from: Abbvie, MSD and Alfasigma, Consultant of: AbbVie, Abiogen, Alfasigma, Biogen, BMS, Celgene, Eli-Lilly, Janssen, MSD, Novartis, Sanofi and Sanofi Genzyme, Speakers bureau: AbbVie, Alfasigma, BMS, Eli-Lilly, Janssen, MSD, Novartis, Sanofi

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 in Juvenile Idiopathic arthritis (JIA), musculoskeletal ultrasound (MSUS) has been proven to be more sensitive than clinical evaluation in detecting articular synovitis. Nevertheless, many studies report a variable percentage of clinically active joints, that are judged normal by ultrasound examination. In absence of a feasible and reliable gold standard for pediatric synovitis (histology or MRI), this point may weaken the confidence in ultrasound, that is nevertheless perceived as an interesting tool, in the management of JIA. Objectives This preliminary study investigates the possibility that sometimes the clinically detected synovitis could be missed by ultrasound, because of its extra-articular localization. Methods 43 consecutive children affected by JIA underwent separated clinical and ultrasound assessments, blindly, in the same day. Patients were followed up in a pediatric Rheumatology Unit. The following clinical data were collected: age, sex, disease duration, subset of JIA, ongoing therapy, previous therapy, disease activity. By MSUS, the synovitis was investigated bilaterally, both in gray scale and power Doppler, in the MCP and subtalar joints, wrists, knees, ankles, in the flexor and extensor tendons of the wrist and hand, in the anterior, medial and lateral tendons of the ankle, in the synovial bursae of knee and ankle. The possible involvement of the entheses was also investigated. The definition of ultrasonographic synovitis was based on the preliminary OMERACT definitions of synovitis in children. The inter and intra observer reproducibility of the MSUS examination was tested, independently, both between two operators and through a second assessment of the stored images. Results 43 children affected by JIA were recruited, in the outpatient clinic of the Regina Margherita Pediatric Hospital of Torino, Italy. They were 9 boys and 34 girls, median age 7,7 (IQR 5,5–10,1), 27 oligoarticular, 11 poliarticular, 4 psoriatic arthritis, 1 undifferentiated arthritis. The median disease duration was 44 months (IQR: 20,5–61,5), 20 patients in remission, 23 with active disease. 774 joints, 1548 synovial sheaths, 430 entheses and 258 synovial bursae were assessed. The physical examination detected inflammation in 54 joints, 33 tendons, 0 entheses, 0 bursae. Ultrasound abnormalities were found in 62 joints, 73 tendons, 8 bursae, 0 entheses. Overall physical examination and MSUS showed good concordance even if MSUS was more sensitive especially in detecting extra-articular locations. Conclusions If the extra-articular locations of synovitis are taken in consideration during the ultrasound examination, there is a good sensitivity of MSUS and a better concordance between clinical and MSUS assessment of JIA. MSUS seems more accurate than physical assessment in detecting the exact position of the inflamed synovial membrane in each anatomical location (joint, synovial sheath, synovial bursa). It could be helpful not only for better addressing the injective procedures, but also for a global quantification of the synovitis (both intra and extra-articular), even if the exact clinical meaning of these ultrasound findings is still unknown, in terms of response to treatments and prognosis. References Magni-Manzoni S. Arthritis and rheumatism. 2009 Nov 15; 61(11):1497–1504. Roth J. Arthritis Care Res (Hoboken). 2016 Oct 16. Disclosure of Interest None declared

In patients with primary antibody deficiencies, subcutaneous administration of IgG (SCIG) replacement is effective, safe, well-tolerated, and can be self-administered at home. A new SCIG replacement at 20% concentration (Hizentra®) has been developed and has replaced Vivaglobin® (SCIG 16%). An observational prospective multi-centric open-label study, with retrospective comparison was conducted in 15 Italian centers, in order to investigate whether and to what extent switching to Hizentra® would affect frequency of infusions, number of infusion sites, patients’ satisfaction, and tolerability in patients previously treated with Vivaglobin® or intravenous immunoglobulins (IVIG). Any variations of dosage, frequency and duration of the infusions, and of number of infusion sites induced by Hizentra® with respect to the former treatment were recorded. Practical advantages and disadvantages of Hizentra®, with respect to the medicinal product formerly used, and the variations in patients’ therapy-related satisfaction were monitored by means of the TSQM (Treatment Satisfaction Questionnaire for Medication); number, frequency, and duration of infectious events and adverse effects were recorded. Eighty-two patients switched to Hizentra®: 19 (23.2%) from IVIG and 63 (76.8%) from Vivaglobin®. The mean interval between infusions was not affected by the shift (7.0 ± 2.0 days with previous treatment versus 7.1 ± 1.2 during Hizentra®). A decrease in the number of infusion sites with Hizentra® was recorded in 12 out of 56 patients for whom these data were available. At 6 months, 89.7% of patients were satisfied with Hizentra®; no difference in terms of effectiveness, side effects, convenience, and global satisfaction was observed. No difference in the incidence of adverse events was reported.

Objectives To estimate the incidence of acute rheumatic fever (ARF) in a metropolitan area of Northern Italy and study how the introduction of the 2015 revised Jones criteria affects the epidemiology in a region with moderate to high incidence of ARF. Study design The incidence of ARF in children 5-14 years old living in the Province of Turin was estimated using low-risk criteria in a 10-year period (group A patients). The proportion of patients fulfilling only high-risk (HR) criteria (group B patients) was also calculated both prospectively (from July 2015 through December 2016) and retrospectively (from January 2007 through June 2015). Results One hundred thirty-five group A patients were identified for an annual incidence of 3.2-9.6 out of 100 000 children. The use of HR criteria identified an additional 28 patients (group B), resulting in a 20.7% increase in the incidence of ARF. Age, sex annual incidence, and seasonal distribution pattern were comparable between group A and group B patients. Conclusions HR criteria should be used for the diagnosis ARF in our region. The application of these criteria led to a 20% increase in patients with the diagnosis of ARF. The characteristics of patients fulfilling only HR criteria are similar to the remaining patients, suggesting that these criteria are sensitive and specific.

The natural history of vertically acquired HCV infection is ill defined. The aim of this study was to outline the natural course of vertical HCV infection in a cohort of untreated children, including rate of spontaneous viral clearance, frequency and features of HCV-related autoimmune disorders. Children with vertical HCV infection were prospectively followed from the first month of life with regular clinical and laboratory assessments. Statistical analysis was performed using Prism 5.0. Forty-five children (median age 12 years, interquartile range 6.9–15.5) were studied. Genotype 1 was predominant (53.3 %). Spontaneous viral clearance was achieved by 12 patients (26.7 %) and associated with genotype 3. Alanine-amino-transferase levels were increased in most children in the first 2 years of life with higher values in those who later cleared the infection. All children were asymptomatic for liver disease. Transient elastography (32 patients) showed mild or moderate fibrosis in nine and two cases, respectively. Non-organ-specific autoantibodies were detected in 24 children (53.3 %) independently of viremia; of these, one developed type-1 diabetes. Cryoglobulinemia was associated with genotype 1 infection and found in 15 subjects (33.3 %): two had low C4 levels and persistent proteinuria. Conclusions: Vertically acquired HCV infection may result in spontaneous clearance in up to 27 % of children. Resolution of infection is higher with genotype 3, usually occurs in preschool age and persists over time. Chronic infection is generally asymptomatic, although hepatomegaly and mild fibrosis may develop. Autoantibodies and cryoglobulins are frequent, whereas the associated clinical manifestations are rare.