Effectiveness and Safety of Biosimilars in Pediatric Non-infectious Uveitis: Real-Life Data from the International AIDA Network Uveitis Registry.

INTRODUCTION: Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU). METHODS: Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE). RESULTS: Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38-5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4-14.9, p = 0.0003). Three minor AEs were reported. CONCLUSIONS: TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05200715.

Clinical features, treatment and outcomes of Italian children with enthesitis-related arthritis and juvenile psoriatic arthritis: a cross-sectional cohort study.

OBJECTIVES: Limited information is available on the clinical features, treatment modalities and outcomes of the juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA). This study was aimed to describe the characteristics of Italian children with ERA and JPsA and to compare them with those of patients with the other categories of JIA. METHODS: Patients were part of a multinational sample included in a study aimed to investigate the prevalence of disease categories, treatment approaches, and disease status in patients from across different geographical areas (EPOCA Study). All patients underwent a retrospective assessment, based on the review of clinical chart, and a cross-sectional evaluation, which included assessment of physician- and parent-reported outcomes and laboratory tests, and recording of ongoing therapies. RESULTS: Of the 9081 children with JIA enrolled in the EPOCA Study, 1300 were recruited at 18 paediatric rheumatology centres in Italy. 45 (3.5%) had ERA and 49 (3.8%) had JPsA. Several remarkable differences in demographic features and frequency of articular and extra-articular manifestations, disease damage, impairment in physical function and health-related quality of life, school-related problems, comorbidities, and ongoing treatments were observed between ERA and JPsA and the other JIA categories. CONCLUSIONS: We described the characteristics of Italian children with ERA and JPsA and highlighted their peculiarities and their differences from the other JIA subsets. These data provide useful insights for future revisions of JIA classification and a benchmarking against which the features from other cohorts may be compared.

"Neuroimmunoendocrinology" in Children with Rheumatic Diseases: How Glucocorticoids Are the Orchestra Director.

The neural, the endocrine, and the immune systems are studied as distinct districts in physiological and pathological settings. However, these systems must be investigated with an integrative approach, while also considering that therapeutic agents, such as glucocorticoids, can induce a reversible or irreversible change of this homeostasis. Children and adolescents affected by rheumatic diseases frequently need treatment with corticosteroids, and the treatment must sometimes be continued for a long time. In the biological era, the treat-to-target strategy allowed a real revolution in treatment, with significant steroid dose sparing or, in many patients, steroid treatment withdrawal. In this review, the impact of glucocorticoids on endocrine, immune, and neurologic targets is analyzed, and the crosstalk between these systems is highlighted. In this narrative review, we explore the reasoning as to why glucocorticoids can disrupt this homeostasis, we summarize some of the key results supporting the impact of glucocorticoids treatment on endocrine, immune, and neurologic systems, and we discuss the data reported in the international literature.

More Children Means More Tumours? We Can Do More to Protect the Health of Our Kids-A Call for a New Epidemiology That Can Change the World.

In encyclopaedic dictionaries published until 1955, the word "tumour" was defined as an "occupational disease suffered by the workers of chemical industries", thus referring to a very specific cause [...].

Incidence and Prevalence of Multisystem Inflammatory Syndrome in Children (MIS-C) in Southern Italy.

Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory syndrome related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection whose epidemiology is not very well known at present. The objective of the study was to better understand the incidence of MIS-C in the Apulia region in southern Italy. Our primary goal was to estimate the incidence of newly identified cases of MIS-C in children aged 0-18 years, during a period of six months, encompassing the second pandemic wave. We also analyzed the characteristics of our cohort in terms of clinical features, treatment, and outcomes. The cumulative incidence of MIS-C was 3.27 per 100,000 residents between 0 and 18 years of age. In our cohort, gastrointestinal, mucocutaneous, and cardiac involvement were the most common clinical features. With our step-up approach to therapy, no patients required intensive care unit (ICU) admission and no cardiac sequelae after 6 months of onset were found in echocardiograms. Conclusion: Our epidemiological study of MIS-C in southern Italy showed unexpectedly overlapping figures with other US studies.

Intra- and Juxta-Articular Osteoid Osteoma Mimicking Arthritis: Case Series and Literature Review.

BACKGROUND: Intra- and juxta-articular osteoid osteomas are rare, representing less than 10% of all osteomas. Compared to the classic diaphyseal or metaphyseal site of long bones, they often have an atypical onset, a longest diagnostic delay, and frequent initial misdiagnoses, with pictures that can mimic inflammatory monoarthritis. We aimed to describe a case series, and to provide a literature review of this uncommon and misleading tumor location. METHODS: We performed a retrospective analysis of patients referred to three pediatric rheumatology centers, with a final diagnosis of articular osteoid osteoma. A review of the literature was additionally conducted. RESULTS: We included 10 patients with a mean age of 14 years. All patients with unusual sites (olecranon fossa, lumbar vertebra, distal phalanx of the toe, fibula) had a misdiagnosis, and cases with initial suspicion of monoarthritis had the longest diagnostic delay, up to 24 months. The literature review confirms the significant risk of misdiagnosis, and an average time from symptom onset to diagnosis ranging from 0.4 to 1.8 years. CONCLUSIONS: Articular osteoid osteoma may mimic arthritis, especially in adolescence. Knowledge of the atypical forms of presentation, and of the clinical and radiological pitfalls, reduces the risk of diagnostic error.

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers.

Introduction: New early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients. Methods: Fourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples. Results: We first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups. Discussion: These data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease.

Preliminary data revealing efficacy of Streptococcus salivarius K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry.

Objective: To evaluate the potential role of Streptococcus salivarius K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction. Patients and methods: The medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months. Results: The number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), p < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [p < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), p < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, p < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis (p < 0.001), oral aphthae (p < 0.001) and cervical lymphadenopathy (p < 0.001) significantly decreased following SSK12. Conclusion: SSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). STUDY DESIGN: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The ß coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). RESULTS: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. CONCLUSIONS: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

Incidence of Non-Melanoma Skin Cancers in Salento (Southern Italy): A 15-Year Retrospective Analysis from the Cancer Registry of Lecce.

BACKGROUND AND OBJECTIVES: Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC) and squamous-cell carcinoma (SCC), as well as a wide range of rare skin tumors. NMSCs is the most frequently diagnosed type of tumor among Caucasians. We aimed at estimating the incidence and mortality of NMSCs in the Salento area (Lecce province, Southern Italy), whose population is assumed to experience heavy and frequent sun exposure due to climatic/environmental factors, both for working and leisure activities. MATERIALS AND METHODS: We computed the incidence of NMSCs in the Province of Lecce by examining the comprehensive real-world data collected by the local cancer registry, which covers all the 830,000 inhabitants, over a period of fifteen years (from 2003 to 2017), with a focus on the latest 5 years (2013-2017) for the analysis of the different histologic morphologies of these tumors. The incidence of NMSCs has been described in terms of absolute frequencies, crude rates and age-adjusted direct standardized rates (DSR). Joinpoint analysis was used to examine temporal trends in the incidence of NMSCs and estimate annual percent changes (APCs). RESULTS: During the period of 2003-2017, the incidence of NMSCs reached a direct standardized rate (DSR) of 162.62 per 100,000 in men (mortality 1.57 per 100,000) and 89.36 per 100,000 in women (mortality 0.52 per 100,000), respectively. The incidence significantly increased among both men and women across the entire period. Basal cell carcinoma (BCC), with its different morphologies, represented about 67.6% of the NMSCs in men (n = 2139 out of a total of 3161 tumors observed between 2013 and 2017) and about 75.8% of the NMSCs in women (n = 1718 out of a total of 2264 tumors from 2013 to 2017), thus accounting for the vast majority of NMSCs. The results are consistent with the literature data carried out both at national and international level. CONCLUSIONS: Proper monitoring of this phenomenon through timely reporting and recording of all new NMSC cases is necessary to develop new preventive strategies.

Prevalence of familial autoimmune diseases in juvenile idiopathic arthritis: results from the international Pharmachild registry.

BACKGROUND: Little is known about the disposition to autoimmune diseases (ADs) among children diagnosed with JIA. In this study, we provide a comprehensive overview of the prevalence of and factors associated with ADs in parents of children with juvenile idiopathic arthritis (JIA). METHODS: Prevalence rates of ADs and 95% Poisson confidence intervals were calculated for parents of JIA patients from the international Pharmachild registry and compared with general population prevalence rates as reported in the literature. Demographic, clinical and laboratory features were compared between JIA patients with and without a family history of AD using χ2 and Mann-Whitney U tests. RESULTS: Eight thousand six hundred seventy three patients were included and the most common familial ADs were psoriasis, autoimmune thyroid disease, rheumatoid arthritis and ankylosing spondylitis. The prevalence of several ADs was higher in parents of the included JIA patients than in the general population. Clinical Juvenile Arthritis Disease Activity Scores at study entry and last follow-up were not significantly different between patients with (n = 1231) and without a family history of AD (n = 7442). Factors associated with familial AD were older age at JIA onset (P < 0.01), Scandinavian residence (P < 0.01), enthesitis-related arthritis, psoriatic arthritis and undifferentiated arthritis (P < 0.01), ANA positivity (P = 0.03) and HLA-B27 positivity (P < 0.01). CONCLUSIONS: Familial AD proves to be a risk factor for JIA development and certain diseases should therefore not be overlooked during family health history at the diagnosis stage. A family history of AD is associated with the JIA category but does not influence the severity or disease course.

Complications of severe acute respiratory syndrome coronavirus 2 infection in children.

PURPOSE OF REVIEW: Although during the initial stages of COVID-19 pandemic, the pediatric population seemed to be less affected, a number of SARS-CoV-2-related manifestations emerged over time, the principal of which is the multisystem inflammatory syndrome in children (MIS-C). Here we provide an update on the main pediatric disorders associated with SARS-CoV-2 infection. RECENT FINDINGS: MIS-C is novel postinfectious manifestation with clinical features similar to Kawasaki disease and characterized by intense systemic inflammation affecting multiple organs. Many children required intensive care therapy because of circulatory shock, usually of myocardial origin. Appropriate treatment with immunomodulatory therapies led to favorable outcomes in most patients, with recovery of overall health and cardiac dysfunction. In addition to MIS-C, a variety of other complications of COVID-19 in children have been described, including thrombotic events, neurologic manifestations, and chilblain-like lesions. There is still uncertainty about the true prevalence of long COVID in children and its distinction from pandemic-related complaints. SUMMARY: The experience gained so far with MIS-C and the other SARS-CoV-2-related complications in children and adolescents will facilitate accurate diagnosis and appropriate treatment. Further studies are needed to elucidate the pathophysiology of MIS-C and to determine the real impact of long-COVID in the pediatric age group.

Canakinumab in systemic juvenile idiopathic arthritis: real-world data from a retrospective Italian cohort.

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.

Intra-articular venous malformations of the knee: a diagnostic challenge.

BACKGROUND: Intra-articular venous malformations (IAVM) are rare benign vascular anomalies that usually affect young patients and most common locate in the knee. The terminology of these lesions is still ill-defined, as they are often termed in the literature as synovial hemangiomas. Early diagnosis can be difficult, because they usually present with nonspecific clinical manifestations that are similar those of other rheumatic diseases, especially juvenile idiopathic arthritis (JIA). CASE SERIES: We conducted a retrospective analysis of five pediatric patients admitted to our units for recurrent swelling of the knee, and compared their characteristics with those of literature reports. The average age at first symptom and time from onset to diagnosis was 3.9 years (range 18 months-7 years) and 3.5 years (range 1-7 years), respectively. In our patients, an initial misdiagnosis of JIA, bleeding disorder or traumatic arthropathy was made. On MRI imaging, the features of the lesion were similar in all patients, and were marked by isointense-to-hypointense signal in T1-weighted images, and hyperintense signal in T2-weighted images. When performed, arthrocentesis led to aspiration of bloody fluid. The diagnosis was confirmed with a biopsy and histopathologic assessment in all patients. Open surgery enabled complete excision of the mass and was followed by stable remission over time in all cases. CONCLUSIONS: Our report highlights the challenges that may be posed by the detection of knee IAVM and the frequent long delay between onset of symptoms and diagnosis. The key elements for early recognition include careful assessment of patient history, demonstration of bloody fluid on arthrocentesis, and proper interpretation of MRI scanning.

Multisystem Inflammatory Syndrome in Children: Unique Disease or Part of the Kawasaki Disease Spectrum?

One of the most intriguing and mysterious phenomena observed during the COVID-19 pandemic has been represented by the occurrence of the multisystem inflammatory syndrome in children and adolescents (MIS-C). Patients with this condition have some overlapping signs and symptoms with those of Kawasaki disease (KD), but also display clinical features that are uncommon or less frequent in this illness, such as diarrhea, abdominal pain and myocardial involvement. The sickest patients may develop multiorgan failure and shock, usually due to myocarditis. Management is based on the administration of intravenous immunoglobulin, glucocorticoids and, in the most severe instances, anakinra. It is still debated whether MIS-C and KD represent different illnesses or are part of the same disease spectrum. The aim of the present review is to analyze critically the evidence in favor of the latter hypothesis and to provide the authors' personal interpretation of the relationship between the two conditions.

Comparison Between Clinical and Ultrasound Assessment of the Ankle Region in Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To compare the frequency of joint and tendon disease on ultrasound (US) and clinical examination, and to investigate agreement between US and clinical evaluation in ankles with clinically active juvenile idiopathic arthritis (JIA). METHODS: US and clinical evaluation were performed independently in the joint and tendon compartments of 105 ankles. Gray-scale (GS) US and power Doppler (PD) US joint abnormalities were scored on a 4-point semiquantitative scale. A joint with a GS score ≥2 and/or a PD score ≥1 was defined as active on US. Agreement was tested using kappa statistics. RESULTS: A total of 163 joints in 89 ankles had active synovitis on US. The tibiotalar (TT) joint was the most commonly affected joint on US and on clinical evaluation. The intertarsal (IT) joint and the subtalar (ST) joint were the second in frequency on US and on clinical evaluation, respectively. Tenosynovitis was found more commonly on US than on clinical evaluation (70.5% and 32.4%, respectively), and was more frequent in the medial and lateral than in the anterior tendon compartment. Isolated tenosynovitis was detected on US in 12 of 105 ankles. Agreement between US and clinical evaluation for detection of active synovitis and tenosynovitis was less than acceptable (κ <0.4). No correlation was found between any feature of active disease recorded on clinical evaluation (joint swelling, tenderness/pain on motion, and restricted motion) and active synovitis on US in the TT joint, ST joint, and IT joint. CONCLUSION: Coupling clinical evaluation with US aids in correctly localizing pathology. US training of practitioners is recommended to manage ankle disease in JIA.

Development and Testing of Reduced Versions of the Manual Muscle Test-8 in Juvenile Dermatomyositis.

OBJECTIVE: To develop and test shortened versions of the Manual Muscle Test-8 (MMT-8) in juvenile dermatomyositis (JDM). METHODS: Construction of reduced tools was based on a retrospective analysis of individual scores of MMT-8 muscle groups in 3 multinational datasets. The 4 and 6 most frequently impaired muscle groups were included in MMT-4 and MMT-6, respectively. Metrologic properties of reduced tools were assessed by evaluating construct validity, internal consistency, discriminant ability, and responsiveness to change. RESULTS: Neck flexors, hip extensors, hip abductors, and shoulder abductors were included in MMT-4, whereas MMT-6 also included elbow flexors and hip flexors. Both shortened tools revealed strong correlations with MMT-8 and other muscle strength measures. Correlations with other JDM outcome measures were in line with predictions. Internal consistency was good (0.88-0.96) for both MMT-4 and MMT-6. Both reduced tools showed strong ability to discriminate between disease activity states, assessed by the caring physician or a parent (P < 0.001), and between patients whose parents were satisfied or not satisfied with illness course (P < 0.001). Responsiveness to change (assessed by both standardized response mean and relative efficiency) of MMT-4 and, to a lesser degree, MMT-6, was slightly superior to that of MMT-8. CONCLUSION: Overall, the metrologic performance of MMT-4 and MMT-6 was comparable to that of the other established muscle strength tools, which indicates that they may be suitable for use in clinical practice and research, including clinical trials. The measurement properties of these tools should be further tested in other patient populations and evaluated prospectively.

Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study.

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.

IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis.

We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)α/ß receptor 2 (IFNAR2) gene presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient's cells, as revealed by the lack of phosphorylation of STAT1 and the lack of induction of interferon-stimulated genes upon ex vivo stimulation with IFNα. HLH has been reported in patients with inborn errors of type I IFN-mediated immune responses following vaccination with live-attenuated viruses. The relation between HLH and defective type I IFN-mediated responses is unclear. We show that in patient's natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected. These data support a role for NK cell function dysregulation and lack of inhibition of IFNγ production as contributors to the development of HLH in patients with impaired type I IFN signaling.