Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

C13orf31 (FAMIN) is a central regulator of immunometabolic function.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

The Multifaceted Immunology of Cytokine Storm Syndrome.

Cytokine storm syndromes (CSSs) are potentially fatal hyperinflammatory states that share the underpinnings of persistent immune cell activation and uninhibited cytokine production. CSSs can be genetically determined by inborn errors of immunity (i.e., familial hemophagocytic lymphohistiocytosis) or develop as a complication of infections, chronic inflammatory diseases (e.g., Still disease), or malignancies (e.g., T cell lymphoma). Therapeutic interventions that activate the immune system such as chimeric Ag receptor T cell therapy and immune checkpoint inhibition can also trigger CSSs in the setting of cancer treatment. In this review, the biology of different types of CSSs is explored, and the current knowledge on the involvement of immune pathways and the contribution of host genetics is discussed. The use of animal models to study CSSs is reviewed, and their relevance for human diseases is discussed. Lastly, treatment approaches for CSSs are discussed with a focus on interventions that target immune cells and cytokines.

Tumor-necrosis factor α-rich environment alters type-I interferon response to viral stimuli in patients with juvenile idiopathic arthritis by altering myeloid dendritic cell phenotype.

The balance between the tumor-necrosis factor α (TNFα) and type-I interferon (T1IFN) pathways is crucial for proper immune function. Dysregulation of either pathway can contribute to autoimmune diseases development. Even though TNFα blockade has shown promising results in various autoimmune diseases, the effect on the balance between TNFα and T1IFN is elusive. We used targeted anti-TNFα therapies in juvenile idiopathic arthritis (JIA) as an experimental approach to study the cross-regulation between TNFα and type-I IFN. We found that TNFα-rich environment affected viral defense through the attenuation of T1IFN responses and affected the phenotype and distribution of myeloid dendritic cells, which are engaged in early viral infections. Anti-TNFα therapy normalized the observed deviations in JIA patients. We hypothesize that the inadequate immune response caused by a high TNFα environment could be projected to more frequent or lengthy viral infections and possibly play a role in the process of JIA disease development.

LACC1 deficiency leading to juvenile arthritis and anemia.

OBJECTIVE: Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1. METHODS: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs. RESULTS: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6. CONCLUSION: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.

T lymphocytes-related cell network in the pathogenesis of juvenile idiopathic arthritis: a key point for personalized treatment.

PURPOSE OF REVIEW: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritis of unknown origin occurring in children under 16 years of age and persisting for at least 6 weeks. Given that JIA is an inflammatory disorder, treatment strategies, including also biologicals, are focused on suppressing excessive inflammation. The finding that different patients display different responses to biological drugs supports the concept that different pathogenic mechanisms can exist in JIA, with specific cellular and molecular mechanisms driving inflammation in each patient. The aim of this review is to highlight the most recent advances in understanding the role of immune cells in JIA pathogenesis. RECENT FINDINGS: This review encompasses the role of the different cell subsets involved in sustaining inflammation in JIA, with a particular emphasis on T cells, as they orchestrate both innate and adaptive auto-reactive immunity in affected joints. SUMMARY: The characterization of the cellular and molecular pathways supporting inflammation will be crucial to design novel therapeutic approaches in the context of personalized medicine.

Novel therapies in juvenile idiopathic arthritis.

PURPOSE OF REVIEW: This review summarises the major novel treatment options for children with juvenile idiopathic arthritis (JIA) since the pandemic, reflecting not only on advancements in therapeutics but also approach to management and research. RECENT FINDINGS: Several recent international paediatric trials have been important in advancing understanding of JIA and furthering available treatment options. Biologic and small molecule agents were demonstrated to be effective and safe in recalcitrant or severe JIA (including extra-articular complications), mirroring the adult equivalent diseases. SUMMARY: Although joint and overall health have vastly improved for young people with JIA, ongoing international collaboration, critical review of treatment strategies and high quality research are essential to optimize outcomes.

Drug therapy in juvenile spondyloarthritis.

PURPOSE OF REVIEW: This review summarizes latest developments in treatment of juvenile spondyloarthritis (JSpA), specifically enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA). RECENT FINDINGS: There has been addition of biologic disease modifying antirheumatic drugs (bDMARDs) beyond tumor necrosis factor inhibitors (TNFi) for JSpA such as IL-17 blockers, IL-23 blockers, and janus activating kinase inhibitors with favorable safety profile. Conducting robust clinical trials for this subpopulation of JIA remains a challenge; extrapolation studies are being used to obtain approval from regulatory agencies. SUMMARY: Newer drug therapies have expanded the scope of treatment for patients with JSpA. bDMARDs such as adalimumab, etanercept, infliximab, and secukinumab have demonstrated clinically significant treatment efficacy in ERA and JPsA. Based on extrapolation studies, intravenous golimumab, etanercept, abatacept, and ustekinumab have gained Food and Drug Administration (FDA) approval for JPsA. Long-term follow-up studies continue to demonstrate acceptable safety profiles. There is need for more real-world data on drug efficacy from Registry studies and research on effective de-escalation strategies.

Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

BACKGROUND: Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1ß-driven disease of unknown etiology. OBJECTIVE: In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease. METHODS: Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signaling reporter assay. RESULTS: Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment. CONCLUSION: Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy.

Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial.

BACKGROUND: Juvenile idiopathic arthritis can be refractory to some or all treatment regimens, therefore new medications are needed to treat this population. This trial assessed the efficacy and safety of baricitinib, an oral Janus kinase 1/2-selective inhibitor, versus placebo in patients with juvenile idiopathic arthritis. METHODS: This phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial was conducted in 75 centres in 20 countries. We enrolled patients (aged 2 to <18 years) with polyarticular juvenile idiopathic arthritis (positive or negative for rheumatoid factor), extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or juvenile psoriatic arthritis, and an inadequate response (after ≥12 weeks of treatment) or intolerance to one or more conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The trial consisted of a 2-week safety and pharmacokinetic period, a 12-week open-label lead-in period (10 weeks for the safety and pharmacokinetic subcohort), and an up to 32-week placebo-controlled double-blind withdrawal period. After age-based dosing was established in the safety and pharmacokinetic period, patients received a once-daily 4 mg adult-equivalent dose of baricitinib (tablets or suspension) in the open-label lead-in period. Patients meeting Juvenile Idiopathic Arthritis-American College of Rheumatology (JIA-ACR) 30 criteria (JIA-ACR30 responders) at the end of the open-label lead-in (week 12) were eligible for random assignment (1:1) to receive placebo or continue receiving baricitinib, and remained in the double-blind withdrawal period until disease flare or up to the end of the double-blind withdrawal period (week 44). Patients and any personnel interacting directly with patients or sites were masked to group assignment. The primary endpoint was time to disease flare during the double-blind withdrawal period and was assessed in the intention-to-treat population of all randomly assigned patients. Safety was assessed in all patients who received at least one dose of baricitinib throughout the three trial periods. For adverse events in the double-blind withdrawal period, exposure-adjusted incidence rates were calculated. The trial was registered on ClinicalTrials.gov, NCT03773978, and is completed. FINDINGS: Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled and received at least one dose of baricitinib (152 [69%] girls and 68 [31%] boys; median age 14·0 years [IQR 12·0-16·0]). 219 patients received baricitinib in the open-label lead-in period, of whom 163 (74%) had at least a JIA-ACR30 response at week 12 and were randomly assigned to placebo (n=81) or baricitinib (n=82) in the double-blind withdrawal period. Time to disease flare was significantly shorter with placebo versus baricitinib (hazard ratio 0·241 [95% CI 0·128-0·453], p<0·0001). Median time to flare was 27·14 weeks (95% CI 15·29-not estimable) in the placebo group, and not evaluable for patients in the baricitinib group (<50% had a flare event). Six (3%) of 220 patients had serious adverse events during the safety and pharmacokinetic period or open-label lead-in period. In the double-blind withdrawal period, serious adverse events were reported in four (5%) of 82 patients (incidence rate [IR] 9·7 [95% CI 2·7-24·9] per 100 patient-years at risk) in the baricitinib group and three (4%) of 81 (IR 10·2 [2·1-29·7]) in the placebo group. Treatment-emergent infections were reported during the safety and pharmacokinetic or open-label lead-in period in 55 (25%) of 220 patients, and during the double-blind withdrawal period in 31 (38%) of 82 (IR 102·1 [95% CI 69·3-144·9]) in the baricitinib group and 15 (19%) of 81 (IR 59·0 [33·0-97·3]) in the placebo group. Pulmonary embolism was reported as a serious adverse event in one patient (1%; IR 2·4 [95% CI 0·1-13·3]) in the baricitinib group in the double-blind withdrawal period, which was judged to be related to study treatment. INTERPRETATION: Baricitinib was efficacious with an acceptable safety profile in the treatment of polyarticular juvenile idiopathic arthritis, extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, and juvenile psoriatic arthritis, after inadequate response or intolerance to standard therapy. FUNDING: Eli Lilly and Company under licence from Incyte.

Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients.

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.

Health Care Utilization and Direct Costs Prior to Subspecialty Care in Children with Chronic Pain Compared with Other Chronic Childhood Diseases: A Cohort Study.

OBJECTIVES: To understand the burden associated with pediatric chronic pain (CP) on the health care system compared with other costly chronic diseases prior to subspecialty care. STUDY DESIGN: In this retrospective cohort study, we assessed all-cause health care utilization and direct health care costs associated with pediatric CP (n = 91) compared with juvenile arthritis (n = 135), inflammatory bowel disease (n = 90), type 1 diabetes (n = 475) or type 2 diabetes (n = 289), anxiety (n = 7193), and controls (n = 273) 2 and 5 years prior to patients entering subspecialty care in Manitoba, Canada. Linked data from physician encounters, emergency department visits, hospitalizations, and prescriptions were extracted from administrative databases. Differences in health care utilization and direct health care costs associated with CP vs the other conditions were tested using negative binomial and zero-inflated negative binomial regression models, respectively. RESULTS: After adjustment for age at diagnosis, sex, location of residence, and socioeconomic status, CP continued to be associated with the highest number of consulted physicians and subspecialists and the highest number of physician billings compared with all other conditions (P < .01, respectively). CP was significantly associated with higher physician costs than juvenile arthritis, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, or controls (P < .01, respectively); anxiety was associated with the highest physician and prescription costs among all cohorts (P < .01, respectively). CONCLUSION: Compared with chronic inflammatory and endocrinologic conditions, pediatric CP and anxiety were associated with substantial burden on the health care system prior to subspecialty care, suggesting a need to assess gaps and resources in the management of CP and mental health conditions in the primary care setting.

JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study.

OBJECTIVES: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment. METHODS: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology. RESULTS: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment. CONCLUSION: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.

Addressing the unmet needs of transitional care in juvenile idiopathic arthritis.

OBJECTIVES: We aimed to comprehensively analyse the available literature to identify the unmet requirements in transitional programs tailored specifically for patients diagnosed with JIA. METHODS: According to published guidance on narrative reviews, a systematic review of the literature on transitional care in rheumatology was conducted. Pertinent documents were collected from reputable databases, such as Web of Science, Scopus, and MEDLINE/PubMed. The search encompassed literature published from the inception of each database until January 2023. RESULTS: In this study, a comprehensive analysis of the findings of 34 studies was conducted. Among these, 12 studies focused on assessing the readiness of adolescents and young adults diagnosed with JIA. Additionally, 18 studies examined the effectiveness of structured transition programs in terms of adherence and satisfaction. Finally, 4 studies investigated disease-related outcomes in this population. CONCLUSION: The need for transitioning children with rheumatic diseases to adult rheumatology services for continued care is clearly evident. However, the absence of established best practice guidelines presents a challenge in facilitating this transition effectively. Although several scoring systems have been proposed to ensure organized and seamless transfers, a consensus has not yet been reached. Furthermore, the socio-economic and cultural variations across countries further complicate the development of universal guidelines for transitioning children with rheumatic diseases. To address these concerns, our objective in conducting this literature review was to emphasize the significance of this issue and identify the specific requirements based on the unmet needs in the transition process.

Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis.

OBJECTIVES: CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with JIA, categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA) or PsA. METHODS: Participants with eoJIA (2-17 years old), ERA or PsA (each 12-17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA ACR 30/50/70/90/100 criteria and ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis DAS (JADAS) ≤1. RESULTS: Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 [n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 (78%) on active treatment]; 84 (66%) completed 120 months' follow-up [32 (25%) on active treatment]. One malignancy (Hodgkin's disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates (events per 100 patient-years) of TEAEs (excluding infections/ISRs) decreased from 193 (173.81) in Year 1 to 9 (27.15) in Year 10; TE infections and serious infections also decreased. Over 45% of participants (n = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 34 (27%) participants achieved JADAS and ACR clinical remission, respectively. CONCLUSIONS: Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit-risk assessment of etanercept in these JIA categories remains favourable. TRIAL REGISTRATION: ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069).

Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH.

CD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (HLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Peripheral blood mononuclear cells from children with inactive systemic juvenile idiopathic arthritis (sJIA, n = 17), active sJIA (n = 27), MAS in sJIA (n = 14), infection-associated HLH (n = 7), and with other forms of sHLH (n = 9) were analyzed by flow cytometry. Compared with patients with active sJIA, in patients with MAS and sHLH of different origins, beside a significant increase in the frequency of CD38high/HLA-DR+CD8+ T cells, we found a significant increase in the frequency of CD8+ T cells expressing the CD4 antigen (CD4dimCD8+ T cells). These cells expressed high levels of the activation markers CD38 and HLA-DR, suggesting they were a subset of CD38high/HLA-DR+CD8+ T cells, as well as of the activation/exhaustion markers CD25, PD1, CD95, and interferon-γ. The frequency of CD4dimCD8+ T cells strongly correlated with most of the laboratory parameters of MAS severity and with circulating levels of CXCL9 and interleukin-18. These findings were confirmed in a prospective replication cohort in which no expansion of any particular T-cell receptor Vß family in CD3+ T cells of patients with sHLH was found. Finally, frequency of CD4dimCD8+, but not of CD38high/HLA-DR+CD8+ T cells, significantly correlated with a clinical severity score, further supporting the involvement of these cells in MAS/sHLH pathogenesis.

Psychiatric Morbidity Is Common Among Children With Juvenile Idiopathic Arthritis: A National Matched Cohort Study.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease that causes joint inflammation and pain. Previous studies have indicated affected mental health and increased risk of psychiatric conditions among patients with JIA. We aimed to explore differences in psychiatric morbidity between children with JIA and their peers. We further studied if parental socioeconomic status (SES) influences the association between JIA and the risk of psychiatric morbidity. METHODS: We used a matched cohort design to estimate the association between JIA and psychiatric disease. Children with JIA, born between 1995 and 2014, were identified in Danish national registers. Based on birth registers, we randomly selected 100 age- and sex-matched children per index child. Index date was the date of the fifth JIA diagnosis code or the date of matching for reference children. End of follow-up was the date of psychiatric diagnosis, death, emigration, or December 31, 2018, whatever came first. Data were analyzed using a Cox proportional hazard model. RESULTS: We identified 2086 children with JIA with a mean age at diagnosis of 8.1 years. Children with JIA had a 17% higher instantaneous risk of a psychiatric diagnosis when compared with the reference group, with an adjusted hazard ratio of 1.17 (95% CI 1.02-1.34). Relevant associations were found only for depression and adjustment disorders. Stratifying our analysis for SES showed no modifying effect of SES. CONCLUSION: Children with JIA had a higher risk of psychiatric diagnoses compared to their peers, especially diagnoses of depression and adjustment disorders. The association between JIA and psychiatric disease did not depend on parental SES.

Association of Infant Breastfeeding and Juvenile Spondyloarthritis: A Case-Control Study.

OBJECTIVE: Given the multifactorial pathogenesis of juvenile spondyloarthritis (JSpA) and evidence of a protective effect in phenotypically similar diseases, we aimed to test whether breastfeeding is associated with the development and disease activity of JSpA. METHODS: This single-center retrospective case-control study included children with JSpA and age- and sex-matched controls with a 1:1 ratio. Univariable and multivariable conditional logistic regression modeling for matched pairs was used to test the association of infant factors with the development of JSpA, including infant nutrition and form of delivery. Linear regression was used to assess the association of JSpA disease activity (JSpA Disease Activity Index with 6 elements [JSpADA6]) at presentation with breastfeeding exposure, form of delivery, and antibiotic exposure. RESULTS: For the 195 case-control matched pairs, the mean age was 13.0 years and 47.7% were female. For breastfeeding, 88.7% of controls and 69.2% of JSpA cases were exposed to breastfeeding of any duration, respectively (P < 0.001). In the multivariable model, exclusive breastfeeding > 6 months was independently and significantly associated with a lower chance of JSpA development (odds ratio 0.47, 95% CI 0.30-0.72; P < 0.001). The median JSpADA6 was not significantly associated with breastfeeding for > 6 months. However, vaginal delivery was significantly associated with a lower JSpADA6 (B = -0.65, 95% CI -1.13 to -0.17; P = 0.008). CONCLUSION: This study suggests that infant factors that affect the microbiome may be associated with the occurrence and disease activity of JSpA at presentation.

School Well-Being and Academic Performance of Children With Juvenile Idiopathic Arthritis: A National Register-Based Study.

OBJECTIVE: We aimed to investigate how school well-being (SWB) and academic performance of children with juvenile idiopathic arthritis (JIA) compare to their peers on a national level using the Danish national registers. Further, we investigated the potential influence of socioeconomic status (SES). METHODS: A population-wide, register-based, cross-sectional study was performed. We compared the results of children with and without JIA in the Danish National Well-Being Questionnaire (DNWQ), the National Danish School Testing (NDST), and their ninth grade (aged approximately 16 yrs) final school marks in Danish and mathematics. The results were analyzed using adjusted ordinal logistic regression (SWB) and linear regression (tests and marks). RESULTS: In separate cohorts, we included a total of 505,340 children answering the DNWQ, 812,461 children with NDST results, and the ninth-grade final marks of 581,804 children. Of these children, 1042, 1541, and 1410, respectively, fulfilled the criteria of JIA. Children with JIA reported SWB comparable to their peers, except for the question "Do you perform well in school?" (odds ratio 0.89, 95% CI 0.81-0.99). In the NDST, the children with JIA in general did just as well as their peers. We found no differences in the ninth-grade final marks in either Danish or mathematics. Stratifying the analyses on SES showed no significant differences in the associations. CONCLUSION: Overall, children with JIA report SWB comparable to that of children without JIA and perform equally well in school as children without JIA.

Severe Features of Systemic Juvenile Idiopathic Arthritis in Patients With Congenital Heart Disease.

OBJECTIVE: To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA). METHODS: We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory, and radiographic data were collected from the medical record and reviewed with each patient's primary medical team. RESULTS: Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy, but all the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n = 5), rash (n = 5), and arthritis (n = 4) developed after surgical intervention in all the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n = 5), elevated interleukin 18 levels (n = 5), baseline eosinophilia prior to initiation of biologic disease-modifying antirheumatic drugs (n = 4), and positivity for HLA-DRB1*15:01 alleles (n = 4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease. CONCLUSION: We identified an association between CHD and severe forms of sJIA. Although these findings will need to be confirmed in larger, multicenter cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD.