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Scientific Reports Sep 2023To explore the genetic characteristics of systemic juvenile rheumatoid arthritis (sJRA) and type 1 diabetes mellitus (T1D). The microarray data of sJRA and T1D from Gene... (Meta-Analysis)
Meta-Analysis
To explore the genetic characteristics of systemic juvenile rheumatoid arthritis (sJRA) and type 1 diabetes mellitus (T1D). The microarray data of sJRA and T1D from Gene Expression Omnibus (GEO) were analyzed. The shared differentially expressed genes (SDEGs) were identified by the Meta-analysis, and genes of extracellular proteins were identified. Then, transcription factors (TFs) and their target genes in SDEGs were obtained by comparing databases from HumanTFDB, and hTFtarget. After that, functional enrichment analyses of the previously identified gene sets were performed by metascape tool. Finally, immune infiltration was analysed by CIBERSORT. We found 175 up-regulated and 245 down-regulated SDEGs, and by constructing a TFs-targeted SDEGs network, 3 key TFs (ARID3A, NEF2, RUNX3) were screened. Functional enrichment analyses and immune infiltration results suggested not only the adaptive immune system but also the innate immune system, and signaling pathways like JAK-STAT are important in the pathogenesis of sJRA and T1D, involving biological processes such as CD4 T cell functions and neutrophil degranulation. This work suggests that innate immune abnormalities also play important roles in sJRA and T1D, CD4 T cell functions, neutrophil degranulation and the JAK-STAT pathway may be involved. The regulatory roles of ARID3A, NEF2, and RUNX3 in this network need to be further investigated.
Topics: Humans; Diabetes Mellitus, Type 1; Janus Kinases; STAT Transcription Factors; Signal Transduction; Genomics; DNA-Binding Proteins; Transcription Factors
PubMed: 37704687
DOI: 10.1038/s41598-023-42209-8 -
Cell Genomics Nov 2023was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined....
was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of . Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by , resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding functional variant drives risk of inflammatory arthritis in children and adults.
PubMed: 38020975
DOI: 10.1016/j.xgen.2023.100420 -
The Journal of Rheumatology Nov 2023To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or...
OBJECTIVE
To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or ABA monotherapy when prior MTX use was either ineffective or not tolerated.
METHODS
Posthoc analysis of 2 phase III trials of subcutaneous (SC) and intravenous (IV) ABA over 2 years in patients with pcJIA (aged 2-17 years). Patients were stratified by treatment with ABA + MTX or ABA monotherapy and further by prior biologic use. Efficacy outcomes included JIA-American College of Rheumatology (JIA-ACR) responses, Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP), and safety. Descriptive pharmacokinetic analyses were also performed.
RESULTS
Efficacy responses (JIA-ACR and JADAS27-CRP) were similar between patients receiving ABA + MTX (n = 310) or ABA monotherapy (n = 99) and persisted over 2 years. Clinical response rates were similar in biologic-naïve patients and prior biologic users; this was independent of MTX use. Across both studies, ABA + MTX and ABA monotherapy displayed similar safety profiles. Pharmacokinetic results revealed similar minimum steady-state trough ABA concentrations between studies. Further, baseline MTX did not influence ABA clearance and was not a significant predictor of JIA-ACR responses.
CONCLUSION
ABA monotherapy (SC and IV) was effective and well tolerated in children with pcJIA when prior MTX use was ineffective or not tolerated. Treatment effects of ABA appear to be independent of MTX coadministration. Consequently, ABA monotherapy can be considered for those with prior biologic therapy if MTX use is inappropriate. (ClinicalTrials.gov: NCT01844518 and NCT00095173).
Topics: Child; Humans; Methotrexate; Abatacept; Arthritis, Juvenile; Antirheumatic Agents; Drug Therapy, Combination; Biological Products; Treatment Outcome
PubMed: 37453737
DOI: 10.3899/jrheum.2022-1320 -
PloS One 2023Various definitions have been proposed for Refractory Disease in people with Rheumatoid Arthritis; however, none were generated for Polyarticular Juvenile Idiopathic...
OBJECTIVE
Various definitions have been proposed for Refractory Disease in people with Rheumatoid Arthritis; however, none were generated for Polyarticular Juvenile Idiopathic Arthritis or involving adult and paediatric multidisciplinary healthcare professionals and patients. The study aim is to redefine Refractory Disease, using Delphi methodology.
METHODS
Three rounds of surveys (one nominal group and two online (2019-2020)) to achieve consensus using a predetermined cut-off were conducted voting on: a) name, b) treatment and inflammation, c) symptoms and impact domains, and d) rating of individual components within domains. Theoretical application of the definition was conducted through a scoping exercise.
RESULTS
Votes were collected across three rounds from Patients, Researchers and nine multi-disciplinary healthcare professional groups (n = 106). Refractory Inflammatory Arthritis was the most popular name. Regarding treatment and inflammation, these were voted to be kept broad rather than specifying numbers/cut-offs. From 10 domains identified to capture symptoms and disease impact, six domains reached consensus for inclusion: 1) Disease Activity, 2) Joint Involvement, 3) Pain, 4) Fatigue, 5) Functioning and Quality of Life, and 6) Disease-Modifying Anti-Rheumatic Drug Experiences. Within these domains, 18 components, from an initial pool (n = 73), were identified as related and important to capture multi-faceted presentation of Refractory Inflammatory Arthritis, specifically in Rheumatoid Arthritis and Polyarticular Juvenile Idiopathic Arthritis. Feasibility of the revised definition was established (2022-2023) with good utility as was applied to 82% of datasets (n = 61) incorporating 20 outcome measures, with two further measures added to increase its utility and coverage of Pain and Fatigue.
CONCLUSION
Refractory Inflammatory Arthritis has been found to be broader than not achieving low disease activity, with wider biopsychosocial components and factors incorporating Persistent Inflammation or Symptoms identified as important. This definition needs further refinement to assess utility as a classification tool to identify patients with unmet needs.
Topics: Humans; Child; Arthritis, Juvenile; Quality of Life; Arthritis, Rheumatoid; Pain; Inflammation; Delphi Technique
PubMed: 37556424
DOI: 10.1371/journal.pone.0289760 -
Frontiers in Immunology 2023IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease...
OBJECTIVE
IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1β secretion. The first objective of our study was to characterize IL-1β-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions and . The second objective was to detect circulating IL-1β-positive MVs in JIA patients.
METHODS
MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1β, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied by measuring VCAM-1, ICAM-1, and E-selectin expression after HUVEC co-culture and factor-Xa generation test was realized. , MVs' ability to recruit leukocytes in a murine model of peritonitis was evaluated. Plasmatic IL-1β-positive MVs were studied in 10 active JIA patients using flow cytometry.
RESULTS
THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1β and bioactive TF. IL-1β-positive MVs expressed P2X7 receptor and released soluble IL-1β in response to ATP stimulation . In mice, MVs induced a leukocyte peritoneal infiltrate, which was reduced by treatment with the IL-1 receptor antagonist. Finally, IL-1β-positive MVs were detectable in plasma from 10 active JIA patients.
CONCLUSION
MVs shed from activated macrophages contain IL-1β, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients.
Topics: Humans; Animals; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Arthritis, Juvenile; Lipopolysaccharides; Receptors, Purinergic P2X7; Macrophages; Caspase 1; Adenosine Triphosphate
PubMed: 38077384
DOI: 10.3389/fimmu.2023.1228122 -
Pediatric Rheumatology Online Journal Jul 2023Resilience has been shown to be associated with better psychological outcomes and ability to cope with negative and traumatic events in the healthcare setting....
BACKGROUND
Resilience has been shown to be associated with better psychological outcomes and ability to cope with negative and traumatic events in the healthcare setting. Therefore, in this study, we aimed to evaluate resilience and its association with disease activity and health-related quality of life (HRQOL) in children with Systemic Lupus Erythematosus (SLE) and Juvenile Idiopathic Arthritis (JIA).
FINDINGS
Patients with diagnoses of SLE or JIA were recruited. We collected: demographic data, medical history and physical examination, physician and patient global health assessments, Patient Reported Outcome Measurement Information System questionnaires, Connor Davidson Resilience Scale 10 (CD-RISC 10), Systemic Lupus Erythematosus Disease Activity Index, and clinical Juvenile Arthritis Disease Activity Score 10. Descriptive statistics were calculated, and PROMIS raw scores were converted to T-scores. Spearman's correlations were performed, with statistical significance set to p < 0.05. 47 study subjects were recruited. The average CD-RISC 10 score in SLE was 24.4, and in JIA was 25.2. In children with SLE, CD-RISC 10 was correlated with disease activity and inversely correlated with anxiety. In children with JIA, resilience was inversely associated with fatigue, and positively correlated with mobility and peer relationships.
CONCLUSIONS
In children with SLE and JIA, resilience is lower than in the general population. Further, our results suggest that interventions to increase resilience may improve the HRQOL of children with rheumatic disease. Ongoing study of the importance of resilience in this population, as well as interventions to increase resilience, will be an important area of future research in children with SLE and JIA.
Topics: Humans; Child; Arthritis, Juvenile; Quality of Life; Lupus Erythematosus, Systemic; Longitudinal Studies; Surveys and Questionnaires
PubMed: 37420184
DOI: 10.1186/s12969-023-00854-3 -
Scientific Reports Oct 2023Uveitis is one of the most common manifestations of juvenile idiopathic arthritis (JIA). Currently, JIA is associated with decreased gut microbiota diversity. Studies...
Uveitis is one of the most common manifestations of juvenile idiopathic arthritis (JIA). Currently, JIA is associated with decreased gut microbiota diversity. Studies confirm that perinatal events can cause aberrant microbial colonization. The objective of this study is to determine if JIA is associated with perinatal events with a secondary focus on these variables to the development of JIA-uveitis. 369 patients with strabismus (n = 200) or JIA (n = 196) were included in the study. Completed surveys (JIA 37; strabismus 18) collected data about birth route, pregnancy and labor complications, JIA medications, and the presence of eye disorders. Analysis indicates that there is no relationship between JIA development and the perinatal events investigated. Similarly, no significance was found between JIA-uveitis and birth route or labor complications. Pregnancy complications, namely gestational diabetes (GD), were statistically higher in the JIA group with uveitis compared to JIA without uveitis. The data from this survey study showed that JIA-uveitis was highly associated with pregnancy complications, particularly with GD. However, no statistically significant association was found between JIA and route of delivery, labor complications, or pregnancy complications. Further studies are needed to understand the ways that GD interrelates with the development of uveitis in JIA patients.
Topics: Humans; Female; Arthritis, Juvenile; Uveitis; Strabismus; Obstetric Labor Complications; Pregnancy Complications
PubMed: 37845273
DOI: 10.1038/s41598-023-44208-1 -
Pediatric Rheumatology Online Journal Jul 2023Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer from disability and disease-related damage. This study aimed to investigate the prevalence...
BACKGROUND
Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer from disability and disease-related damage. This study aimed to investigate the prevalence of disability and damage, and identify the factors associated with articular and extra-articular damage in children and adolescents with JIA in a resource-restricted setting in Thailand.
METHODS
This cross-sectional study enrolled JIA patients during June 2019-June 2021. Disability was assessed using the Child Health Assessment Questionnaire (CHAQ) and Steinbrocker classification criteria. Damage was evaluated using the Juvenile Arthritis Damage Index (JADI) and the modified-JADI (mJADI) tools.
RESULTS
There were 101 patients (50.5% female) with median age of 11.8 years. Median disease duration was 32.7 months. Enthesitis-related arthritis (ERA) was the most common subtype (33.7%), followed by systemic JIA (25.7%). Thirty-three (32.7%) patients had delayed diagnosis ≥ 6 months. Moderate to severe disability was found in 20 (19.8%) patients. Patients with Steinbrocker functional classification > class I were seen in 17.9%. Thirty-seven (36.6%) patients had articular damage. Extra-articular complications were observed in 24.8%. Growth failure and striae were the most common complications in 7.8%. Leg-length discrepancy was documented in 5.0%. Ocular damage was found in 1 patient with ERA. Multivariable logistic regression analysis revealed Steinbrocker functional classification > class I (aOR: 18.1, 95% CI: 3.9-84.6; p < 0.001), delayed diagnosis ≥ 6 months (aOR: 8.5, 95%CI: 2.7-27.0; p < 0.001), and ERA (aOR: 5.7, 95%CI: 1.8-18.3; p = 0.004) as independent predictors of articular damage. Systemic corticosteroids use was the independent predictor of extra-articular damage (aOR: 3.8, 95%CI: 1.3-11.1; p = 0.013).
CONCLUSIONS
Disability and disease-related damage was identified in one-fifth and one-third of JIA patients. Early detection and treatment are essential for preventing permanent damage.
Topics: Humans; Adolescent; Child; Female; Male; Arthritis, Juvenile; Cross-Sectional Studies; Southeast Asian People; Thailand; Face
PubMed: 37430274
DOI: 10.1186/s12969-023-00852-5 -
Inflammation and Regeneration Jul 2023This study aimed to provide an overview of ultrasonographic cartilage evaluation in patients with rheumatoid arthritis (RA) and identify research gaps in the utilization... (Review)
Review
BACKGROUND
This study aimed to provide an overview of ultrasonographic cartilage evaluation in patients with rheumatoid arthritis (RA) and identify research gaps in the utilization of cartilage evaluation.
METHODS
The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. A systematic literature search of the PubMed, Embase, and Cochrane Library databases was conducted for articles published up to July 2022 using the search term variations of "cartilage," "ultrasonography," and "rheumatoid arthritis." Studies that included patients with RA who underwent cartilage evaluation by ultrasonography were selected. Articles published in languages other than English and about juvenile idiopathic arthritis were excluded.
RESULTS
Twenty-nine articles were identified. Most were cross-sectional studies (86%), mainly involving the metacarpophalangeal (55%) and knee (34%) joints. Assessments were performed using quantitative, binary, and semi-quantitative methods in 15, 10, and 15 studies, respectively. Reliability assessments were conducted in 10 studies, which showed feasible reliability but were limited to the finger joints. The validity assessment was validated in one study each that compared cartilage thickness measurements with cadaveric specimens and histological and semi-quantitative methods with surgical specimens, respectively. Comparisons with conventional radiography were also performed in six studies, which showed significant correlations. However, there was heterogeneity in the examination and assessment methods, and no adequate longitudinal evaluation was conducted.
CONCLUSION
This review highlights the need for further research and validation of ultrasonographic cartilage assessment in patients with RA.
PubMed: 37403142
DOI: 10.1186/s41232-023-00286-2 -
Hereditary Cancer in Clinical Practice Dec 2023Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 - 50%. Around 40-60% of JPS... (Review)
Review
BACKGROUND
Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 - 50%. Around 40-60% of JPS cases are caused by disease-causing variants (DCV) in SMAD4 or BMPR1A genes, of which SMAD4 accounts for 20-30%.
OBJECTIVES
To characterise genotype-phenotype correlations between sites and types of variants within SMAD4 to JPS phenotypes, to inform diagnosis, screening, and management of JPS.
SEARCH METHODS
Online search databases utilised included Ovid MEDLINE, Embase Classic + Embase and PubMed, using search terms classified by MeSH on Demand. Adjacency operators, word truncation and Boolean operators were employed. 110 articles were included in the review, collating 291 variants from the literature.
RESULTS
In SMAD4 + JPS patients, most variants are located around SMAD4's MH2 domain (3' end). Extracolonic involvement, massive gastric polyposis and a more aggressive phenotype have been associated with SMAD4 + JPS, predisposing to gastric cancer. This has contributed to an overall higher incidence of GI cancers compared to other genes causing JPS, with DCVs mostly all within the MH2 domain. Genetically related allelic disorders of SMAD4 also have variants in this region, including hereditary haemorrhagic telangiectasia (HHT) alongside SMAD4 + JPS, and Myhre syndrome, independent of JPS. Similarly, with DCVs in the MH2 domain, Ménétrier's disease, hypertrophic osteoarthropathy and juvenile idiopathic arthritis have been seen in this population, whereas cardiac pathologies have occurred both alongside and independently of SMAD4 + JPS with DCVs in the MH1 domain.
CONCLUSION
Truncating and missense variants around the MH2 region of SMAD4 are most prevalent and pathogenic, thus should undergo careful surveillance. Given association with extracolonic polyposis and higher GI cancer risk, endoscopic screening should occur more frequently and at an earlier age in SMAD4 + JPS patients than in patients with other causative genes, with consideration of Ménétrier's disease on upper GI endoscopy. In addition, HHT should be evaluated within 6 months of diagnosis, alongside targeted clinical examination for extraintestinal manifestations associated with SMAD4 + JPS. This review may help modify clinical diagnosis and management of SMAD4 + JPS patients, and aid pathogenicity classification for SMAD4 DCVs through a better understanding of the phenotypes.
PubMed: 38066625
DOI: 10.1186/s13053-023-00267-z