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Behçet’s syndrome (BS) is a rare chronic multi-systemic inflammatory disorder that usually involves adults between third and fourth decades of life, while pediatric and juvenile onset are relatively rare. BS young patients (YP) often develop a full-blown disease late after onset, requiring careful diagnostic workup and regular follow-up while they grow up. In this regard, the purpose of transitional programs is to ensure continuous high-quality care to YP with chronic conditions, providing them with the skills necessary to become independent and empowered adults able to chronically self-manage their disease. EULAR/PReS released the first set of standards and recommendations for transitional care (TC) of YP with juvenile-onset rheumatic diseases, but the appropriate timing for transition, the tools to evaluate patients’ readiness, and indicators of transition plans effectiveness still need to be identified. Although little is known regarding TC in BS, it is easy to assume that BS YP will benefit from developmentally and disease-specifically appropriate transition plans, which may promote continuity of care, improve perceived quality of life and prevent poor disease outcomes. This perspective article discusses the key concepts and the goals of TC, addressing the potential challenges and opportunities of TC for YP with BS in clinical practice.

Objective: Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF. Methods: A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed. Results: 23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (χ20.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(χ2 27.5 p

Abstract Introduction Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally described as mimicker of polyarteritis nodosa, with immunodeficiency and early-onset stroke. Methods A systematic review according to PRISMA approach, including all articles published before the 31st of August 2021 in Pubmed and EMBASE database was performed. Results The search identified 90 publications describing 378 unique patients (55.8% male). To date 95unique mutations have been reported. The mean age at disease onset was 92.15 months (range 0–720 months), 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The most frequent clinical characteristics described were cutaneous (67.9%), haematological manifestations (56.3%), recurrent fever (51.3%), neurological as stroke and polyneuropathy (51%), immunological abnormalities (42.3%), arthralgia/arthritis (35.4%), splenomegaly (30.6%), abdominal involvement (29.8%), hepatomegaly (23.5%), recurrent infections (18.5%), myalgia (17.9%), kidney involvement (17.7%) etc. Patients with skin manifestations were older than the others (101.1 months SD ± 116.5, vs. 75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (64.1 months SD ± 75.6 vs. 133.1 SD ± 133.1, p

BackgroundThe treatment of multisystem inflammatory syndrome in children unresponsive to first-line therapies (IVIG and/or steroids) is challenging. The effectiveness of IL-1 receptor antagonist, anakinra, is debated.Patients and methodsWe conducted an anonymous retrospective multicenter study on MIS-C patients treated with anakinra in Italy from January 2020 to February 2021. Our study outcomes included the percentage of patients who required further therapeutic step-up, the percentage of patients who experienced fever resolution within 24 h and a reduction of CRP by half within 48 h, and the percentage of patients who developed Coronary Artery Anomalies (CAA) during follow-up.Results35 cases of MIS-C were treated in 10 hospitals. Of these, 13 patients started anakinra while in the ICU, and 22 patients started anakinra in other wards. 25 patients (71.4%) were treated with corticosteroids at a starting dose 2–30 mg/Kg/day plus IVIG (2 g/Kg), 10 patients (28.6%) received only corticosteroids without IVIG. Anakinra was administered intravenously to all patients in Group A (mean dose 8 mg/Kg/day), and subcutaneously in Group B (mean dose 4 mg/Kg/day). Only two patients required further treatment step-up and no patients developed CAA after receiving anakinra. The most commonly observed side effect was an increase in ALT, occurring in 17.1% of patients.ConclusionsIn this retrospective cohort of severe MIS-C patients treated with anakinra we report favorable clinical outcomes with a low incidence of side effects. The simultaneous use of steroids ± IVIG in these patients hinders definitive conclusions regarding the need of IL-1 inhibition in MIS-C treatment.

This narrative review aims to report the main clinical manifestations, therapeutic strategies, outcomes, and complications of acute SARS-CoV-2 infection in childhood and to summarize the data relating the SARS-CoV-2 vaccination efficacy and safety in pediatric age. SARS-CoV-2 infection mostly occurs asymptomatically in the pediatric population, while multisystem inflammatory syndrome in children (MIS-C) represents the most severe coronavirus disease 2019 (COVID-19)-related illness, a life-threatening event with a high morbidity rate. After the development of SARS-CoV-2 vaccines and their subsequent approval in children, the rate of infection as well as the number of its related complications have shown a drastic decrease. Fully vaccinated children are protected from the risk of developing a severe disease and a similar protective role has been observed in the reduction of complications, in particular MIS-C. However, long-lasting immunity has not been demonstrated, booster doses have been required, and reinfection has been observed. With regards to vaccine safety, adverse events were generally mild to moderate in all age groups: local adverse events were the most commonly reported. Nevertheless, a potential association between SARS-CoV-2 vaccine and the subsequent development of inflammatory manifestations has been suggested. Myocarditis has rarely been observed following vaccination; it appeared to be more frequent among adolescent males with a mild clinical course leading to a complete recovery. SARS-CoV-2 vaccine-related MIS-C cases have been described, although a univocal definition and an exact time interval with respect to vaccination has not been reported, thus not establishing a direct causal link. Current evidence about COVID-19 vaccination in children and adolescents suggest that benefits outweigh potential risks. Long-term data collection of the post-authorization safety surveillance programs will better define the real incidence of SARS-CoV-2 vaccine-related complications in the pediatric population.

Background: Childhood chronic non-infectious uveitis (cNIU) is a challenging disease that needs close monitoring. Slit lamp evaluation (SLE) is the cornerstone of ophthalmological evaluation for uveitis, but it is affected by interobserver variability and may be problematic in children. Laser flare photometry (LFP), a novel and objective technique, might be used in children with uveitis. Aim: The aim of this study was to attempt the use of LFP in cNIU clinical practice. Methods: Children, attending the Rheumatology Unit and who were scheduled to receive ophthalmological evaluation, were prospectively enrolled to concomitantly receive SLE and LFP. SLE was performed blind to LFP measure. Demographic, laboratory, clinical, and ophthalmology data were collected. Results: A total of 29 children (58 eyes) were enrolled, including 3 with juvenile idiopathic arthritis without uveitis (JIA-no-U), 15 with JIA-associated uveitis (JIA-U), and 11 with idiopathic chronic uveitis (ICU). We observed significantly higher LFP values in the eyes of children with uveitis compared to the others (10.1 IQR 7.1–13.6 versus 6.2 IQR 5.8–6.9, p = 0.007). Accordance between the SLE and LFP measures, at baseline (ρ.498, p < 0.001) and during the follow-up (LFP II ρ 0.460, p < 0.001, LFP III ρ 0.631, p < 0.001, LFP IV ρ 0.547, p = 0.006, LFP V ρ 0.767, p = 0.001), was detected. We evaluated significant correlation between LFP values and the presence of complications (ρ 0.538, p < 0.001), especially with cataract formation (ρ 0.542, p < 0.001). Conclusions: In this cohort, LFP measurements showed a good correlation with SLE. LFP values showed a positive correlation with the presence of complications. LFP might be considered as a reliable objective modality to monitor intraocular inflammation in cNIU.

Neurological manifestations related to SARS-CoV-2 infection in adults have been largely reported since the beginning of the pandemic. Subsequent large-scale studies involving children confirmed the occurrence of neurological symptoms associated with SARS-CoV-2 infection also among paediatric patients, especially in the context of paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS). At this regard, we report the challenging case of a 10-month-old baby with PIMS-TS complicated by acute cerebral oedema successfully treated with intravenous immunoglobulins, corticosteroids and anakinra. Our results, combined with the evidence of larger case series suggest that higher inflammatory burden is more frequent in patients with neuro PIMS-TS. As regards neuroimaging, neuroimmune disorders are found to be more common during acute COVID-19, MERS is more frequent during PIMS-TS. Distinct immune mechanisms may underlie these different types of neurological involvement, which are yet to be understood. Further studies are required to better define the physiopathology of neuro PIMS-TS and its possible therapeutical implications.

Camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome is a rare genetic disease characterized by tetrad camptodactyly, noninflammatory arthropathy, coxa vara deformity, and pericardial effusion. Arthropathy typically affects large joints and presents with joint swelling in the absence of other signs of inflammation. We described the case of a girl affected by CACP syndrome caused by a novel compound heterozygous variant in proteoglycan 4 gene (c.2831_2832insT; c.3892C > T) and associated with temporomandibular involvement. The patient received treatment with intra-articular hyaluronic acid injections, which presented rapid but transient improvements of pain and range of motion. A literature review of previously reported CACP patients has been performed. Of the patients. 69.2% (101 out of 146) were Middle Eastern, and 65.7% (96) were consanguineous. The median age of onset was 24 months (interquartile range of 12–36 months), and median age of diagnosis was 96 months (interquartile range of 48–156 months). Arthropathy was always present, mainly involving hips (95.2%), knees (92.4%), wrists (87.7%), elbows (79.5%), and ankles (57.5%). Camptodactyly and pericardial effusion were described, respectively, in 97.3% (142) and 15.1% (22) of patients. The main radiological findings were coxa vara (95.2%), femoral changes (64.4%), intraosseus cysts (14.4%), and bone erosion (5%). Of the patients, 32.9% (48) had received a previous juvenile idiopathic arthritis diagnosis. CACP syndrome can be easily misdiagnosed with juvenile idiopathic arthritis. A prolonged lack of response to immunosuppressive therapy associated with typical clinical and radiological features should prompt consideration of this rare syndrome.

Abstract Immune response to biologics treatment, while widely reported, yet fails to correlate with clinical outcomes and assay to assay comparison is often not possible. Hence, we developed a new peptide based-detection assay to stratify pediatric patients with juvenile idiopathic arthritis (JIA) or chronic non-infectious uveitis (CNU) and monitor anti-drug antibodies (ADAbs) formed as part of an immune response to treatment with the fully human monoclonal therapeutic antibody Adalimumab. Adalimumab derived synthetic peptides were optimized for maximum immunogenicity and were tested by SP-ELISA on a development cohort of 18 JIA and CNU treated patients. The two best performing peptides able to differentiate patient groups were selected for evaluation with a larger scale ELISA testing on a total of 29 sera from pediatric patients with JIA or CNU. The results of this peptide-based assay were compared to an in-house developed SPR biosensor ADAbs assay and a commercially available bridging ELISA. The first peptide, termed HC3, was able to positively detect ADAbs in 7 out of the 29 sera, while the second peptide, called LC3, was able to detect ADAbs in 11 out of 29 sera in the evaluation group. Following statistical data evaluation, it has been found that the detection of ADAbs using the peptide-based ELISA assay positively correlates with disease progression and remission. Two synthetic peptides derived from Adalimumab may provide a beneficial tool to clinicians for monitoring patient response to such treatment and taking informed decisions for treatment alternatives.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic hyperinflammatory disorder that is associated with a hypercoagulable state and a higher risk of thrombotic events (TEs). We report the case of a 9-year-old MIS-C patient with a severe course who developed a massive pulmonary embolism that was successfully treated with heparin. A literature review of previous TEs in MIS-C patients was conducted (60 MIS-C cases from 37 studies). At least one risk factor for thrombosis was observed in 91.7% of patients. The most frequently observed risk factors were pediatric intensive care unit hospitalization (61.7%), central venous catheter (36.7%), age >12 years (36.7%), left ventricular ejection fraction 5 times the upper limit of normal values (71.9%), mechanical ventilation (23.3%), obesity (23.3%), and extracorporeal membrane oxygenation (15%). TEs may concurrently affect multiple vessels, including both arterial and venous. Arterial thrombosis was more frequent, mainly affecting the cerebral and pulmonary vascular systems. Despite antithrombotic prophylaxis, 40% of MIS-C patients developed TEs. Over one-third of patients presented persistent focal neurological signs, and ten patients died, half of whom died because of TEs. TEs are severe and life-threatening complications of MIS-C. In case with thrombosis risk factors, appropriate thromboprophylaxis should be promptly administered. Despite proper prophylactic therapy, TEs may occur, leading in some cases to permanent disability or death.

BackgroundOur study aimed to evaluate the efficacy of Tocilizumab and Abatacept for treating Childhood Chronic non-infectious Uveitis (CCU), resistant to anti-tumor necrosis factor (anti-TNF) treatment.MethodsThis is a monocentric retrospective charts review study (January 2010–April 2021) recruiting CCU, refractory to anti-TNF. To be included, children should have active uveitis at the time of Tocilizumab (8 mg/kg, every 4 weeks) or Abatacept (10 mg/kg, every 4 weeks). The main outcome was the achievement of ocular remission on treatment defined as the absence of flares for ≥ 6 months.ResultsIn this study, 18 patients with CCU (14 F), previously treated with Methotrexate and Adalimumab, were enrolled: 15 had juvenile idiopathic arthritis (JIA) (83.3%), 2 idiopathic (11.1%), and 1 Behçet (5.6%). Furthermore, ten patients received Abatacept and 8 patients received Tocilizumab. The mean duration of treatment on Abatacept was 31.6 months (SD ± 30.8), on Tocilizumab 25.25 months (SD ± 17.8). In total, 13 children (72.2%) achieved remission, with a better remission rate for the Tocilizumab group (8/8) compared to the Abatacept group (5/10) (χ2 5.53, p = 0.019). No difference was evaluated between the two groups in the proportion of patients who showed flares during the treatment (2/6 Abatacept vs. 1/8 Tocilizumab). A significant difference was evaluated in the proportion of patients who flared after treatment discontinuation: 3/3 Abatacept vs. 0/3 Tocilizumab (χ2 3.8, p = 0.025).ConclusionEven though this is a monocentric retrospective study, in a relatively small group, our study suggests a superior efficacy of Tocilizumab over Abatacept for treating anti-TNF refractory CCU.

Abstract Background Influenza is the most frequent cause of acute upper respiratory tract infections during winter season. Although rare, neurological manifestations are known to occur during influenza infection and approximatively three-quarters of cases are in children. In this study, we aimed to characterize the burden and clinical spectrum of influenza-associated encephalopathy and encephalitis in children admitted at a tertiary pediatric hospital in Italy over two influenza seasons (2017–2019). Methods We retrospectively analyzed clinical, laboratory, instrumental data and outcome of patients discharged with ICD9-CM 487.0 code. Results Fifteen children (13.1% of those discharged with a diagnosis of influenza infection in the study period), had influenza-associated central nervous system (CNS) manifestations. Eight patients (53.3%) were diagnosed as influenza encephalitis, 7 (46.7%) as influenza encephalopathy. Median age was 27 months. In children under 2 years of age (40% of all cases) altered consciousness was the most frequent neurological manifestation while respiratory symptoms were present at admission in all cases. Younger children also required intensive care support more frequently. Five subjects (33.3%) presented comorbidity. None of the patients had received seasonal influenza vaccination. The median time from onset of respiratory signs to onset of neurological manifestations was 24 h. Cerebrospinal fluid (CSF) analysis was normal in most patients and polymerase chain reaction for influenza virus RNA on CSF, when performed, was negative in all samples. Neuroradiological investigations, performed in 5 children, reported cortical and subcortical white matter signal alterations. Oseltamivir was administered only in 2 cases. Fourteen patients recovered without sequelae, and only a 2-year-old girl had minimal impairment in fine motor skills at discharge. Conclusions All children presenting acute neurological features during influenza season should be evaluated for influenza-associated CNS complications even if the respiratory involvement is mild. Absence of underlying diseases or other risk factors are not protective factors against CNS influenza-associated complications. The lack of CSF pleocytosis does not exclude CNS involvement. Children under 2 years of age are at higher risk of requiring intensive care support.

Introduction: Enthesitis-related Arthritis (ERA) is a specific category of juvenile idiopathic arthritis (JIA) characterized by axial and/or peripheral arthritis, and enthesitis, although other different extra-articular manifestations may encompass its clinical spectrum.Materials and Methods: In order to examine if ERA-JIA with extra-articular involvement may represent a different entity from ERA without extra-articular involvement, we performed a retrospective, observational, monocentric study, in a cohort of ERA patients followed between 2001 and September 2020 at the Pediatric Rheumatology Unit of Meyer Children Hospital of Florence. We analyzed the demographic, clinical, laboratory and imaging data at the disease onset, as well as after 3, 6, and 12 months follow up.Results: We have enrolled 53 patients, 33 males. At the time of diagnosis, average age was 10.9 years, 53 patients had active arthritis and 25 active enthesitis. The middle foot involvement was present in 20 patients. Twenty-five children achieved clinical remission on medication. Extra-articular manifestations were observed in 14 patients, of whom 3 had inflammatory bowel disease, 5 uveitis, one uveitis associated with Crohn disease, 4 SAPHO syndrome, one celiac disease. The cohort was stratified according to the presence/absence of extra-articular manifestations. It was observed that middle foot involvement was more frequent in patients with no extra-articular manifestations (18/39 vs. 2/14; χ2 = 4.45, p = 0.05). Additionally, patients presenting extra-articular manifestation needed more frequently (12/14 vs. 21/39, χ2= 4.45, p = 0.05), and preciously (months: 3.7 ± 5.4 vs. 16.7 ± 26.5, p = 0.02), treatment with biologic agents. Finally, these patients achieved belatedly (months: 31.6 ± 32.3 vs. 22.9 ± 18.3, p = 0.01) and less frequently (3/14 vs. 22/39; χ2= 5.50, p = 0.03) the clinical remission on medication. Eventually, extra-articular involvement inversely correlated with the middle-foot arthritis (ρs −0.29, p = 0.03), the chance to achieve remission on medication (ρs −0.31 e p = 0.02), as well as the chance to keep overall remission, with and without medication (ρs −0.28, p = 0.04).Conclusion: In our cohort, children diagnosed with ERA-JIA at the onset of disease and then developed extra-articular manifestations show the absence of middle foot involvement and worse prognosis with an early need for the use of biologic agents, and overall low chance to achieve remission.

Refractory Kawasaki disease (KD) is related to a major risk of coronary arteries abnormalities and its treatment is not standardized. In this regard, anakinra (ANA), an interleukin (IL)-1 receptor antagonist, represents an emerging therapeutic option. We report two cases of children, diagnosed with KD, nonresponsive to two doses of intravenous immunoglobulins, successfully treated with ANA, without a prior use of steroids. Patient 2 developed a coronary dilatation, that improved significantly after ANA therapy. Our experience highlights IL-1 blockade effectiveness in reducing KD inflammation and suggests ANA adoption as second-line therapy, with a timesaving and steroid-sparing strategy. Our results, combined with the evidence of the IL-1 key role in KD and coronary arteritis pathogenesis and to the recent clinical evidence reported by the KAWAKINRA trial, encourage an earlier recourse to ANA in patients with refractory KD, in order to fight inflammation, and to treat and prevent the development of coronary artery aneurysms. Further studies are needed to better define the place of IL-1 blockade in KD step-up treatment.

Interleukin 1 (IL-1), a central mediator of innate immunity, is considered a master cytokine of local and systemic inflammation. IL-1 has emerged as pivotal in the pathogenesis of autoinflammatory diseases (AIDs), and blockade of its pathway has become a crucial target for therapy. Anakinra (ANA), a recombinant IL-1β receptor antagonist, was the first anti-IL-1 agent employed in clinical practice. ANA is currently approved for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and cryopyrin-associated autoinflammatory syndrome. It has also been successfully used for off-label treatment of various monogenic, polygenic, or undefined etiology systemic AIDs. This review describes currently available evidence for the off-label use of ANA in pediatric rheumatologic diseases. Specifically, the use of ANA in Kawasaki disease, idiopathic recurrent pericarditis, Behçet disease, monogenic AIDs, undifferentiated AIDs, chronic non-bacterial osteomyelitis, macrophage activation syndrome, and febrile infection-related epilepsy, in terms of its safety and efficacy. In selected pediatric rheumatic disorders, the off-label administration of ANA appears to be effective and safe. In order to control severe and/or relapsing disease, ANA should be considered as a valuable treatment option in children suffering from rare inflammatory diseases. However, currently available data consist of retrospective studies and short case series; thus, randomized controlled trials and larger series with long-term follow up are mandatory to better assess the efficacy and cost effectiveness of ANA in these challenging patients.