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Abstract Background Juvenile idiopathic arthritis (JIA) is the most common pediatric chronic rheumatic disease, which requires constant follow-up over the years, due to relapses during its progression. To maintain a good quality of life, it is important to limit admissions as far as possible. With the development of a Diagnostic Therapeutic Assistance Pathway (DTAP), we aim to select patients with suitable clinical conditions to be moved from routine hospital management to day care or outpatient treatment, evaluating the number of patients to whom this would apply. Methods Monocentric study regarding admissions for JIA between 2014 and 2016 in a Pediatric Unit of a university hospital in Milan. Through an analysis of the medical records, relevant information was extracted and collected in a Microsoft™ Excel database; starting from the data collected during the first year, a DTAP was prepared for patients with active arthritis and appropriate clinical conditions. Results The study includes data from 223 JIA hospitalization cases involving 127 patients. Applying DTAP criteria, 32% patients would have avoided admissions and 23% would have been admitted less frequently. The data concerning the activities of the Unit for JIA patients showed a relevant drop in the number of hospitalizations since 2015, from 89 in 2014 to 66 and 68 in 2015 and 2016 respectively. Conclusion The opportunity offered by DTAP, has suggested feasible changes in hospitalization management and it’s use would promote the possibility of treating the children without hospitalization, or minimizing it. In conclusion DTAP application is a priority for the continuous improvement of clinical practice and quality of life for patients and their families.

Objectives: To determine features and frequency of ultrasound (US)-detected tenosynovitis in ankles with clinically active disease and to investigate whether its detection may affect the achievement of inactive disease in patients with new-onset juvenile idiopathic arthritis (JIA)., Methods: The study included children with new-onset JIA and clinically active disease of the ankle. Based on US, patients were stratified as having isolated arthritis or as having tenosynovitis irrespective of the presence of concomitant arthritis in the ankle. Estimation of patients who were able to achieve clinically inactive disease 6 months after starting treatment was assessed by the Kaplan-Meier method. Cox model was used to calculate hazard ratio (HR) and 95% confidence interval (CI). Reliability of US was tested using kappa statistic., Results: Forty-five patients were recruited. On US, tenosynovitis of the ankle was detected in 28 patients (62.2%); isolated arthritis was found in 17 patients (37.8%). The medial and lateral tendon compartments were the tendon sites most frequently inflamed. Patients with tenosynovitis had similar likelihood of those without tenosynovitis to achieve clinically inactive disease (60.7% and 58.8%, respectively; HR 1.12, 95%CI:0.51-2.45). In the subanalysis excluding patients who were given biologics, the probability of experiencing inactive disease was slightly higher for patients with tenosynovitis compared to those without (64.7% and 54.5%, respectively; HR 1.56, 95%CI: 0.58-4.24). The rate of US reliability was high., Conclusions: US-detected tenosynovitis is frequent in ankles with clinical arthritis at JIA onset but does not impair the chance of achieving clinically inactive disease in the early disease phase.

Objective: Our objective was to develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis, based on subjective disease state assessment by the treating pediatric rheumatologist., Methods: The cutoff definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, six methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, the Youden index, 90% specificity, maximum agreement, and receiver operating characteristic curve analysis. Sixty percent of the patients were assigned to the definition cohort, and 40% were assigned to the validation cohort. Cutoff validation was conducted by assessing discriminative ability., Results: The sJADAS10 cutoffs that separated ID from MDA, MDA from MoDA, and MoDA from HDA were ≤2.9, ≤10, and >20.6, respectively. The cutoffs discriminated strongly among different levels of pain, between patients with and without morning stiffness, and among patients whose parents judged their disease status as remission or persistent activity or flare or were satisfied or not satisfied with current illness outcome., Conclusion: The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts and are therefore suitable for use in clinical trials and routine practice., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome., Study Design: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified., Results: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes., Conclusions: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Vascular events account for a considerable burden of morbidity and mortality in Behçet syndrome (BS). Thrombosis occurs in 1.8-21 % pediatric BS patients, even if the real prevalence is still largely unknown., Objectives: To report clinical features and outcomes of pediatric BS patients with thrombosis and to compare the demographic and clinical characteristics of BS patients with and without thrombosis., Methods: Retrospective data collection of BS patients with thrombosis (T+) included in the EUROFEVER registry. BS patients without thrombosis (T-), belonging to the same rheumatology units, were matched in a 2:1 ratio., Results: 37 T+ were compared to 74 T- patients. At onset, ICBD criteria fulfillment was higher in the T- group (p = 0.015). Caucasian patients were more often T-, Turkish patients were more frequent in T+ group (p = 0.002). At onset, pustulosis was most frequently observed in the T- (p < 0.001) as well as gastrointestinal symptoms (p < 0.001) and ocular involvement (p = 0.022). Neurological symptoms were more often described in T+ (p = 0.034). As for T+, thrombosis was reported at BS presentation in 8/37 (21.6 %). For the T + e patients who developed thrombosis later, oral aphthosis (p = 0.003), genital aphthosis (p = 0.014) were more frequently observed at BS onset, while pustulosis (p = 0.005) and fever (p = 0.043) coexisted with thrombosis. Thrombosis was mainly venous (26/37,70.3 %), involving the cerebral sinuses (21/37, 56.8 %). After thrombosis, 35/37 (94.6 %) T+ patients received an immunomodulatory treatment compared with 16/29 (55.2 %) pre-thrombosis. A recurrence was reported in 6/31(19.4 %)., Conclusion: Thrombosis was reported at BS presentation in one fifth of cases. Pustolosis and fever were more frequently concomitant to thrombosis. Sinus veins were the most frequent site., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Juvenile Systemic Connective Tissue Diseases (JSCTD) are a heterogeneous group of chronic autoimmune diseases, associated with dyslipidemia and increased cardiovascular risk are related. Studies from the last 10 years, from 2013 to 2022, on lipid profiles in JSCTD were collected. Different studies on lipid profiles in children affected by JSCTD were selected, because the aim is to analyze the cardiovascular risk and the possibility of atherosclerosis in these patients in whom, sometimes, corticosteroid therapies and immunosuppressants increase the state of dyslipidemia. Several studies have shown that autoimmune diseases with an inflammatory substrate also share abnormalities in lipid profile and increased cardiovascular risk. Specifically, associations have been found between Juvenile Systemic Connective Tissue Diseases and elevated triglycerides, TC-C (Total Cholesterol), LDL-C (Low-Density Lipoprotein), low HDL-C (High-Density Lipoprotein), and increased risk of developing diseases such as myocardial infarction, peripheral vascular disease, pulmonary and arterial hypertension, and atrial fibrillation. Supplementation with alpha-linolenic acid (ALA) on the other hand has also been analyzed with positive results in reducing inflammatory parameters, such as IL-6 (Interleukin-6), CRP (C-reactive protein), and fasting glucose, in subjects with dyslipidemia. These observations suggest that supplementation with ALA, an omega-3 precursor, may positively modulate both the inflammatory status and dyslipidemic conditions in patients with autoimmune disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bertoni, Mazzocchi, Leone, Agostoni and Filocamo.)

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.

Objectives: To investigate clinical features associated with lack of response to MTX in juvenile idiopathic arthritis associated uveitis (JIA-U)., Methods: Clinical records of JIA-U patients were retrospectively reviewed. Differences among variables were assessed by Mann-Whitney and χ 2 or Fisher's exact tests as appropriate. Association between predictors and requirement of a biological disease modifying antirheumatic drug (bDMARD) was evaluated by univariate Cox regression analysis and Kaplan-Meier curves. A multivariable logistic model was applied to estimate strength of association, adjusting for potential confounders., Results: Data from 99 JIA-U patients treated with MTX were analysed (82.8% female), with a mean follow up of 9.2 years and a mean age at uveitis onset of 5.7 years. In 65 patients (65.7%) at least one bDMARD to control uveitis was required. Children requiring a bDMARD for uveitis had lower age at JIA and uveitis onset, more frequent polyarticular course, higher frequency of bilateral uveitis at onset and higher prevalence of systemic steroids' use. Despite similar frequency of ocular damage at onset, MTX non responders showed a higher percentage of ocular damage at last visit. Younger age at JIA onset, polyarticular course and a history of systemic steroids' use resulted independent factors associated to lack of response to MTX at Cox regression analysis. Kaplan-Meier curves and the multivariate model confirms the independent role of both polyarticular course and systemic steroids' use., Conclusions: Younger age at JIA onset, polyarticular course and a history of systemic steroids' use are predictors of a worse response to MTX in JIA-U., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Juvenile systemic lupus erythematosus (jSLE) is a complex inflammatory autoimmune disorder. In the last decades, genetic factors and activation pathways have been increasingly studied to understand their potential pathogenetic role better. Genetic and transcriptional abnormalities directly involved in the type I interferon (IFN) signaling cascade have been identified through family-based and genome-wide association studies. IFNs trigger signaling pathways that initiate gene transcription of IFN-stimulated genes through the activation of JAK1, TYK2, STAT1, and STAT2. Thus, the use of therapies that target the IFN pathway would represent a formidable advance in SLE. It is well known that JAK inhibitors have real potential for the treatment of rheumatic diseases, but their efficacy in the treatment of SLE remains to be elucidated. We report the case of a 13-year-old girl affected by jSLE, carrying a novel heterozygous missense variant on Three prime Repair EXonuclease 1 ( TREX1 ), successfully treated with baricitinib on top of mofetil mycophenolate. The TREX1 gene plays an important role in DNA damage repair, and its mutations have been associated with an overproduction of type 1 interferon. This report underlines the role of translational research in identifying potential pathogenetic pathways in rare diseases to optimize treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Rossano, Conti, Bocca, Volpi, Mastrangelo, Cavalli, Gattorno, Minoia and Filocamo.)

Objectives: The aim of this work is to describe the clinical manifestations at onset and during follow-up in a monocentric cohort of patients with juvenile systemic lupus erythematosus (jSLE) from the Paediatric Rheumatology group of the Milan area (PRAGMA)., Methods: Patients were retrospectively included in case of i) SLE diagnosis according to the 1997 American College of Rheumatology or the 2012 SLICC classification criteria and ii) disease onset before 18 years., Results: Among the 177 recruited patients (155 females), haematologic involvement was the most common disease manifestation (75%), followed by joint and cutaneous involvements (70% and 57%, respectively). Renal disease was observed in 58 patients (32.8%), neurological complications in 26 cases (14.7%). Patients presented most commonly 3 clinical manifestations (32.8%), while 2 organ involvements were identified in 54 patients (30.5%) and 4 in 25 subjects (14.1%). The 49 patients with disease onset <10 years had less commonly articular involvement (p=0.02), while patients aged >14.8 years displayed less neurological manifestations (p=0.02). At a median follow-up of 118 month, the disease progressed in 93 patients, with a median of 2 new manifestations per patient. Low complement at diagnosis predicted new clinical manifestations (p=0.013 for C3 and p=0.0004 for C4). The median SLEDAI at diagnosis was 13; SLEDAI was substantially similar at 6 months, decreased at 12 months to remain stable at 18 months and further reduce at 24 months (p<0.0001)., Conclusions: These data from a large jSLE monocentric cohort allow gaining further insights into a rare disease with a still high morbidity burden.

Background: The 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 Methods: We 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., Results: 35 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., Conclusions: In 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., Competing Interests: GF is a consultant for SOBI, GS and MM received an unrestricted educational Grant from SOBI, for a project not related to MIS-C. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Licciardi, Covizzi, Dellepiane, Olivini, Mastrolia, Lo Vecchio, Monno, Tardi, Mauro, Alessio, Filocamo, Cattalini, Taddio, Caorsi, Marseglia, LaTorre, Campana, Simonini, Ravelli and Montin.)

Objective: IgA vasculitis (IgAV) (formerly Henoch-Schönlein Purpura, HSP) rarely causes severe skin lesions in children. The purpose of the research was to determine whether severe skin manifestations were associated with a more severe disease course., Methods: Severe cutaneous manifestations were defined as presence of hemorrhagic vesicles, bullae, ulcerations and/or necroses. Data were collected retrospectively from 12 international tertiary university medical centers., Results: A total of 64 patients with the most severe skin changes in IgAV/HSP and median (Q 1 , Q 3 ) age of 8.08 (5.08, 11.92) years at the disease onset were compared with 596 IgAV/HSP patients without these manfiestations and median (Q 1 , Q 3 ) age of 6.33 (4.50, 8.92) years. The patients with severe cutaneous manifestations were older in comparison to other patients with IgAV/HSP (p<0.001), they developed nephritis more frequently (40.6% vs. 20.6%, p = 0.001) with worse outcome of renal disease (p = 0.001). This group of patients also had higher frequencies of severe gastrointestinal complications like hematochezia, massive bleeding and/or intussusception (29.3% vs. 14.8%, p<0.001). d-dimer concentrations were significantly higher in these patients (4.60 mg/L vs. 2.72 mg/L, p = 0.003) and they had more frequent need for treatment with systemic glucocorticoids (84.4% vs. 37.2%, p<0.001) in comparison with the control group. Further multivariate analysis showed that severe cutaneous changes were associated with higher risk of developing nephritis [OR=3.1 (95%CI 1.04-9.21), p = 0.042] and severe gastrointestinal complications [OR=3.65 (95%CI 1.08-12.37), p = 0.038]., Conclusion: Patients with IgAV/HSP and severe skin manifestations had a more severe clinical course and more frequently required glucocorticoids compared to classic IgAV/HSP patients., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T-lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single-cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single-cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4 + and CD8 + T cells, those characterized by PD-1 expression were clonally expanded tissue-resident memory (Trm)-like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Objective: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission., Study Design: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission., Results: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission., Conclusions: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Raggi, Bartolucci, Cangelosi, Rossi, Pelassa, Trincianti, Petretto, Filocamo, Civino, Eva, Ravelli, Consolaro and Bosco.)

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 β 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to investigate the effectiveness of corticosteroid therapy for children suffering from Sydenham chorea (SC)., Methods: The design of the study was observational, retrospective and conducted at the single center of the Rheumatology Unit of Policlinic Hospital of Milan, Italy, from May 1995 to May 2022. All data about the patients were collected from medical records., Results: From a total of 59 patients enrolled in the study (44 females and 15 males; median age 9.3 years, range 7.4-10.6 years), 49 were eligible for primary outcome analysis (10 patients were excluded due to incomplete data). Overall, 75% of patients received steroid therapy, while the remaining cases were treated with symptomatic drugs, including neuroleptics and antiseizure drugs. We found that the duration of chorea was significantly shorter in patients treated with corticosteroids in comparison to those receiving symptomatic treatment (median time: 31 vs. 41 days, p = 0.023). Additionally, patients with arthritis at the onset of the disease had a longer duration of chorea than those without arthritis (median time 90.5 vs. 39 days, p = 0.02). We also found that chorea recurred in 12% of the patients and seemed to be linked to a younger age at onset ( p = 0.01)., Conclusions: The study suggests that corticosteroid therapy can lead to a faster resolution of SC when compared to neuroleptics and antiseizure drugs treatment.

The latest studies identified the histone deacetylase (HDAC) class of enzymes as strategic components of the complex molecular machinery underlying inflammation in cystic fibrosis (CF). Compelling new support has been provided for HDAC6 isoform as a key player in the generation of the dysregulated proinflammatory phenotype in CF, as well as in the immune response to the persistent bacterial infection accompanying CF patients. We herein provide in vivo proof-of-concept (PoC) of the efficacy of selective HDAC6 inhibition in contrasting the pro-inflammatory phenotype in a mouse model of chronic P. aeruginosa respiratory infection. Upon careful selection and in-house re-profiling (in vitro and cell-based assessment of acetylated tubulin level through Western blot analysis) of three potent and selective HDAC6 inhibitors as putative candidates for the PoC, we engaged the best performing compound 2 for pre-clinical studies. Compound 2 demonstrated no toxicity and robust anti-inflammatory profile in a mouse model of chronic P. aeruginosa respiratory infection upon repeated aerosol administration. A significant reduction of leukocyte recruitment in the airways, in particular neutrophils, was observed in compound 2-treated mice in comparison with the vehicle; moreover, quantitative immunoassays confirmed a significant reduction of chemokines and cytokines in lung homogenate. This effect was also associated with a modest reduced bacterial load after compound 2-treatment in mice compared to the vehicle. Our study is of particular significance since it demonstrates for the first time the utility of selective drug-like HDAC6 inhibitors in a relevant in vivo model of chronic P. aeruginosa infection, thus supporting their potential application for reverting CF phenotype., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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 Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the frequency in which the physician provides a global assessment of disease activity (PhGA) >0 and an active joint count (AJC)=0 in children with juvenile idiopathic arthritis (JIA) and search for determinants of divergence between the two measures., Methods: Data were extracted from a multinational cross-sectional dataset of 9966 patients who had JIA by International League of Associations for Rheumatology criteria, were recruited between 2011 and 2016, and had both PhGA and AJC recorded by the caring paediatric rheumatologist at the study visit. Determinants of discordance between PhGA>0 and AJC=0 were searched for by multivariable logistic regression and dominance analyses., Results: The PhGA was scored >0 in 1647 (32.3%) of 5103 patients who had an AJC of 0. Independent associations with discordant assessment were identified for tender or restricted joint count >0, history of enthesitis, presence of active uveitis or systemic features, enthesitis-related or systemic arthritis, increased acute phase reactants, pain visual analogue scale (VAS)>0, and impaired physical or psychosocial well-being. In dominance analysis, tender joint count accounted for 35.43% of PhGA variance, followed by pain VAS>0 (17.72%), restricted joint count >0 (16.14%) and physical health score >0 (11.42%)., Conclusion: We found that many paediatric rheumatologists did not mark a score of 0 for patients who they found not to have active joints. The presence of pain in joints not meeting the definition of active joint used in JIA was the main determinant of this phenomenon., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: We performed a pilot study in order to investigate the feasibility of an electromyography (EMG)-scoring protocol for the assessment of disease activity in juvenile idiopathic inflammatory myopathies (JIIM)., Methods: Children with JIIM followed up in a tertiary-level care center underwent standardized clinical, laboratory, and EMG assessment. An EMG-scoring protocol was devised by a consensus panel including a pediatric neurophysiologist and two pediatric rheumatologists, based on a combined score obtained as the sum of (1) the presence of denervation signs (fibrillation potentials) and (2) motor unit remodeling (mixed pattern of short- and long-duration motor unit action potentials). The EMG-scoring protocol was then validated following the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter for outcome measures in rheumatology and the consensus-based standards for the selection of health measurement instruments methodology., Results: Thirteen children (77% females) were included in the study, with a median age of 10 years (interquartile range: 7-17 years) and median disease duration of 11.8 months (interquartile range: 2.1-44.5). A total of 39 EMG examinations were evaluated. A strong positive association between a standardized tool for muscle strength assessment and the combined score was observed. No significant associations were found with both creatine kinase and erythrocyte sedimentation rate levels., Discussion: Our EMG-scoring protocol is the first standardized and reproducible tool for the neurophysiologic evaluation and grading of muscle involvement in patients with JIIM and could provide relevant additional information in the assessment and follow-up of these rare conditions., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2020, American College of Rheumatology.)

Objective: To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA)., Study Design: International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS., Results: Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab., Conclusions: The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To build a prediction model for uveitis in children with JIA for use in current clinical practice., Methods: Data from the international observational Pharmachild registry were used. Adjusted risk factors as well as predictors for JIA-associated uveitis (JIA-U) were determined using multivariable logistic regression models. The prediction model was selected based on the Akaike information criterion. Bootstrap resampling was used to adjust the final prediction model for optimism., Results: JIA-U occurred in 1102 of 5529 JIA patients (19.9%). The majority of patients that developed JIA-U were female (74.1%), ANA positive (66.0%) and had oligoarthritis (59.9%). JIA-U was rarely seen in patients with systemic arthritis (0.5%) and RF positive polyarthritis (0.2%). Independent risk factors for JIA-U were ANA positivity [odds ratio (OR): 1.88 (95% CI: 1.54, 2.30)] and HLA-B27 positivity [OR: 1.48 (95% CI: 1.12, 1.95)] while older age at JIA onset was an independent protective factor [OR: 0.84 (9%% CI: 0.81, 0.87)]. On multivariable analysis, the combination of age at JIA onset [OR: 0.84 (95% CI: 0.82, 0.86)], JIA category and ANA positivity [OR: 2.02 (95% CI: 1.73, 2.36)] had the highest discriminative power among the prediction models considered (optimism-adjusted area under the receiver operating characteristic curve = 0.75)., Conclusion: We developed an easy to read model for individual patients with JIA to inform patients/parents on the probability of developing uveitis., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Harlequin ichthyosis (HI) is the most severe phenotype of autosomal recessive congenital ichthyosis. Juvenile Idiopathic Arthritis (JIA) represents a heterogenous group of disorders all sharing the clinical manifestation of chronic arthritis. Association of HI and chronic arthritis has been reported in few cases., Case Presentation: We report the case of a child with HI who developed a severe form of chronic polyarthritis during the first years of life, treated with repeated multiple joint injections, methotrexate and etanercept with good response and without any adverse events., Conclusion: The reported case and the literature review highlighted the presence of a peculiar severe seronegative polyarthritis with early onset in a series of patients with HI, suggesting that polyarthritis may be a specific manifestation of HI, rather than a rare combination of two separate conditions.

Background: Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. MAIN BODY: as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed., Conclusions: we propose a document that will help physicians to diagnose and treat MIS-C patients. Given the level of evidence available and the methodology used, this document should not be interpreted as a guideline; the final decision about the optimal management should still be taken by the caring physician, on an individual basis.

Background: Immunomodulants have been proposed to mitigate severe acute respiratory syndrome coronavirus 2-induced cytokine storm, which drives acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19)., Objective: We sought to determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation., Methods: A secondary analysis of prospective observational cohort studies was carried out at an Italian tertiary health care facility. COVID-19 patients consecutively hospitalized (February 25, 2020, to March 30, 2020) with hyperinflammation (ferritin ≥1000 ng/mL and/or C-reactive protein >10 mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO 2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO 2 :FiO 2 ratio, Charlson index, baseline mechanical ventilation, hospitalization to inclusion lapse) risks were calculated (Cox proportional regression model)., Results: A total of 120 COVID-19 patients with hyperinflammation (median age, 62 years; 80.0% males; median PaO 2 :FiO 2 ratio, 151; 32.5% on mechanical ventilation) were evaluated. Of these, 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 13.9% in treated patients and 35.6% in controls (Kaplan-Meier plots, P = .005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared with controls (hazard ratio, 0.33, 95% CI, 0.15-0.74, P = .007, and HR, 0.18, 95% CI, 0.07-0.50, P = .001, respectively). No significant differences in bloodstream infections or laboratory alterations were registered., Conclusions: Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized controlled trials including the use of either agent alone are needed to confirm these results., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO., Methods: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected., Results: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries., Conclusions: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.

Objective: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity., Methods: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant., Results: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease., Conclusion: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

COVID-19 is a complex and heterogeneous disease. The pathogenesis and the complications of the disease are not fully elucidated, and increasing evidence shows that SARS-CoV-2 causes a systemic inflammatory disease rather than a pulmonary disease. The management of hospitalized patients in COVID-19 dedicated units is advisable for segregation purpose as well as for infection control. In this article we present the standard operating procedures of our COVID-19 high dependency unit of the Policlinico Hospital, in Milan. Our high dependency unit is based on a multidisciplinary approach. We think that the multidisciplinary involvement of several figures can better identify treatable traits of COVID-19 disease, early identify patients who can quickly deteriorate, particularly patients with multiple comorbidities, and better manage complications related to off-label treatments. Although no generalizable to other hospitals and different healthcare settings, we think that our experience and our point of view can be helpful for countries and hospitals that are now starting to face the COVID-19 outbreak.

Coronavirus disease 19 is a global healthcare emergency with a high lethality rate. Relevant inflammatory cytokine storm is associated with severity of disease, and IL1 inhibition is a cornerstone treatment for hyperinflammatory diseases. We present here the case of a patient with critical COVID-19 successfully treated with IL-1 receptor antagonist (anakinra)., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value <0.1). Next-generation sequencing showed a rare c.709A > T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)