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Rheumatology International Jul 2023Systemic juvenile idiopathic arthritis (S-JIA) is a rare but potentially life threatening autoinflammatory condition of childhood. Given the limited data on S-JIA from...
Systemic juvenile idiopathic arthritis (S-JIA) is a rare but potentially life threatening autoinflammatory condition of childhood. Given the limited data on S-JIA from the Australasian region, we investigated the epidemiological characteristics and long-term disease outcome in S-JIA. All hospitalised patients under the age of 16 years registered with ICD-10-AM code M08.2 in in the period 1999-2014 were identified in longitudinally linked administrative health data across all Western Australian (WA) hospitals. Incidence and point prevalence estimate were per 100,000 population with Poisson regression to analyse the incidence trend. Readmissions with S-JIA as primary diagnosis were considered flares with rates for flare and other complication reported per 100 person years with 95% confidence intervals (CI). Annual S-JIA incidence was 0.61/100,000 (CI 0.28-1.25) (46 incident cases, 71.7% girls, median age 6.5 years) and stable over time as S-JIA point prevalence reached 7.15/100,000 (CI 5.29-7.45) at the end of study. Most incident cases were diagnosed in winter and spring, but documented preceding infections were rare. During a median follow-up of 8 years, disease flares occurred in 24% of patients with higher flares rate in boys (58.3; CI 44.5-74.9) than girls (14.7; CI 9.9-20.9). No deaths occurred and arthroplasty was the main, but uncommon S-JIA complication (4%). However, readmission (86.3; CI 76.4-97.2) and ED visit (73.3; CI 64.2-83.4) rates for illnesses other than S-JIA were substantial. S-JIA is as rare in WA as in other regions and while s-JIA incurred no deaths in the era of biologics, it associated with a significant long-term burden of (co-) morbidity.
Topics: Male; Female; Humans; Child; Adolescent; Arthritis, Juvenile; Western Australia; Australia; Comorbidity; Biological Products
PubMed: 36988674
DOI: 10.1007/s00296-023-05318-1 -
Pediatric Rheumatology Online Journal May 2024Juvenile Idiopathic Arthritis (JIA) is a condition that occurs when individuals under the age of 16 develop arthritis that lasts for more than six weeks, and the cause...
BACKGROUND
Juvenile Idiopathic Arthritis (JIA) is a condition that occurs when individuals under the age of 16 develop arthritis that lasts for more than six weeks, and the cause is unknown. The development of JIA may be linked to serum metabolites. Nevertheless, the association between JIA pathogenesis and serum metabolites is unclear, and there are discrepancies in the findings across studies.
METHODS
In this research, the association between JIA in humans and 486 serum metabolites was assessed using genetic variation data and genome-wide association study. The identification of causal relationships was accomplished through the application of univariate Mendelian randomization (MR) analysis. Various statistical methods, including inverse variance weighted and MR-Egger, were applied to achieve this objective. To ensure that the findings from the MR analysis were trustworthy, a number of assessments were carried out. To ensure the accuracy of the obtained results, a range of techniques were utilised including the Cochran Q test, examination of the MR-Egger intercept, implementation of the leave-one-out strategy, and regression analysis of linkage disequilibrium scores. In order to identify the specific metabolic pathways associated with JIA, our primary objective was to perform pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes.
RESULTS
Two-sample summary data MR analyses and sensitivity analyses showed that five metabolites were significantly causally associated with JIA, including two risk factors-kynurenine (odds ratio [OR]: 16.39, 95% confidence interval [CI]: 2.07-129.63, p = 5.11 × 10) and linolenate (OR: 16.48, 95% CI: 1.32-206.22, p = 0.030)-and three protective factors-3-dehydrocarnitine (OR: 0.32, 95% CI: 0.14-0.72, p = 0.007), levulinate (4-oxovalerate) (OR: 0.40, 95% CI: 0.20-0.80, p = 0.010), and X-14,208 (phenylalanylserine) (OR: 0.68, 95% CI: 0.51-0.92, p = 0.010). Furthermore, seven metabolic pathways, including α-linolenic acid metabolism and pantothenate and CoA biosynthesis, are potentially associated with the onset and progression of JIA.
CONCLUSION
Five serum metabolites, including kynurenine and 3-dehydrocarnitine, may be causally associated with JIA. These results provide a theoretical framework for developing effective JIA prevention and screening strategies.
Topics: Humans; Arthritis, Juvenile; Mendelian Randomization Analysis; Genome-Wide Association Study; Child; Polymorphism, Single Nucleotide; Kynurenine
PubMed: 38724970
DOI: 10.1186/s12969-024-00986-0 -
Arthritis Research & Therapy Sep 2022Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis; however, the mechanisms by which they contribute to disease progression are not well...
BACKGROUND
Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis; however, the mechanisms by which they contribute to disease progression are not well described. Previous studies demonstrated that rheumatoid arthritis FLS are heterogeneous, and subpopulations with transformed, aggressive phenotypes cause invasive and destructive disease activity. We employ single-cell RNA-sequencing (scRNA-seq) to investigate JIA FLS heterogeneity and gene expression that distinguishes JIA subtypes.
METHODS
JIA FLS cell lines from three persistent oligoarticular, three pre-extension oligoarticular, and three polyarticular subtypes were cultured. scRNA-seq was performed by Genewiz according to 10 × Genomics Chromium protocols. SeuratR package was used for QC, analysis, and exploration of data.
RESULTS
FLS are heterogeneous and have characteristics of fibroblasts, chondrocytes, and smooth muscle cells. The chondrocyte-like subpopulation is the predominant cell type and percentages of this subpopulation increase with disease severity. Despite overlapping subpopulations, the chondrocyte-like cells have unique genetic fingerprints that distinguish between JIA subtypes. LRRC15, GREM1, and GREM2 are overexpressed in chondrocyte-like cells from persistent oligoarticular JIA FLS compared to pre-extension oligoarticular JIA FLS. S100A4, TIMP3, and NBL1 are overexpressed in pre-extension oligoarticular JIA FLS compared to polyarticular JIA FLS. CRLF1, MFAP5, and TNXB are overexpressed in persistent oligoarticular JIA FLS compared to polyarticular JIA FLS.
CONCLUSIONS
We found biologically relevant differences in gene expression between JIA subtypes that support a critical role for FLS in pathogenesis. We also demonstrate that gene expression within the chondrocyte-like subpopulation can be used to distinguish between these subtypes.
Topics: Arthritis, Juvenile; Chromium; Fibroblasts; Humans; Membrane Proteins; RNA; Single-Cell Analysis; Synoviocytes
PubMed: 36167601
DOI: 10.1186/s13075-022-02913-8 -
The Journal of Clinical Investigation Nov 2023Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights...
Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.
Topics: Adult; Humans; Child; Arthritis, Juvenile; Biomarkers; Lung Diseases; Interferons; Genomics
PubMed: 37733441
DOI: 10.1172/JCI166741 -
International Journal of Molecular... Jul 2021Monocytes (Mos) and macrophages (Mφs) are key players in the innate immune system and are critical in coordinating the initiation, expansion, and regression of many... (Review)
Review
Monocytes (Mos) and macrophages (Mφs) are key players in the innate immune system and are critical in coordinating the initiation, expansion, and regression of many autoimmune diseases. In addition, they display immunoregulatory effects that impact inflammation and are essential in tissue repair and regeneration. Juvenile idiopathic arthritis (JIA) is an umbrella term describing inflammatory joint diseases in children. Accumulated evidence suggests a link between Mo and Mφ activation and JIA pathogenesis. Accordingly, topics regarding the signals and mechanisms regulating Mo and Mφ activation leading to pathologies in patients with JIA are of great interest. In this review, we critically summarize recent advances in the understanding of how Mo and Mφ activation is involved in JIA pathogenesis and focus on the signaling pathways and mechanisms participating in the related cell activation processes.
Topics: Animals; Arthritis, Juvenile; Humans; Macrophage Activation; Macrophages; Monocytes; Signal Transduction
PubMed: 34360720
DOI: 10.3390/ijms22157960 -
Zeitschrift Fur Rheumatologie Feb 2022Still's syndrome includes systemic juvenile idiopathic arthritis (sJIA) and the adult form of Still's disease (adult-onset Still's disease, AOSD). Except for age, there... (Review)
Review
Still's syndrome includes systemic juvenile idiopathic arthritis (sJIA) and the adult form of Still's disease (adult-onset Still's disease, AOSD). Except for age, there are many similarities between sJIA and AOSD. A biphasic disease model is currently put forth. At disease onset, autoinflammation predominates, which is caused by dysregulation of the innate immune system. Later on, the disease can progress to a chronic-articular form, which is predominantly mediated by the adaptive immune system and is consequently due to autoimmunity. The "window-of-opportunity" hypothesis is based on this biphasic model and supports the assumption that an early, targeted therapy with cytokine blockade can prevent disease progression to chronic destructive arthritis. Macrophage activation syndrome (MAS) is a serious complication of the so-called cytokine storm during the systemic phase of the disease. Clinically, there are many similarities between sJIA and AOSD. Recurrent fever, a fleeting, salmon-colored rash, and arthralgia/arthritis are common signs and symptoms of both sJIA and AOSD. The few differences are mainly related to the therapies and their side effects in children versus adults. In addition, the contribution of genetics to pathogenesis is more pronounced in sJIA compared to AOSD, but there are also smooth transitions in this respect and both diseases are heavily influenced by exogenous factors such as microbial triggers. Future research aspects could include additional investigation of these triggers such as viruses, bacteria, or dysbiosis of the human microbiome.
Topics: Adult; Arthritis, Juvenile; Child; Cytokines; Humans; Joints; Macrophage Activation Syndrome; Still's Disease, Adult-Onset
PubMed: 34735597
DOI: 10.1007/s00393-021-01117-w -
Pediatric Rheumatology Online Journal May 2023Oligoarticular juvenile idiopathic arthritis (oligo-JIA) is considered as an antigen-driven lymphocyte-mediated autoimmune disease. Natural antibodies (NAbs) are...
BACKGROUND
Oligoarticular juvenile idiopathic arthritis (oligo-JIA) is considered as an antigen-driven lymphocyte-mediated autoimmune disease. Natural antibodies (NAbs) are pre-immune antibodies produced in the absence of exogenous antigen stimulation, participating in both, innate and adaptive immunity. Considering their major immunoregulatory role in homeostasis and autoimmune pathogenesis, we designed this study to further elucidate their role in oligo-JIA pathogenesis.
METHODS
Seventy children with persistent oligo-JIA and 20 healthy matched controls were enrolled in the study. Serum IgM and IgA antibodies against human G-actin, human IgG F(ab΄)2 fragments and the hapten TriNitroPhenol (TNP) as well as the total concentration of serum IgM and IgA were measured by in-house enzyme-immunoassays. Kolmogorov-Smirnov normality test, Kruskal-Wallis H and Mann-Whitney tests were used to assess data distribution, and significant differences of non-parametric data between groups of the study. Backward regression analysis was used to analyze the effect of multiple factors (age, gender, disease activity, anti-nuclear antibody positivity, presence of uveitis) on continuous dependent variables (activities and activity/ concentration ratios of IgM and IgA NAbs).
RESULTS
The ratios of IgA anti-TNP, anti-actin and anti-F(ab΄) levels to total serum IgA concentration were found to be significantly increased in patients with oligo-JIA compared to healthy subjects. Significantly elevated levels of IgM anti-TNP antibodies were also found in children with inactive oligo-JIA compared to those of children with active disease and of healthy controls. In the presence of anterior uveitis, IgM anti-TNP levels were significantly higher than in patients without uveitis or in healthy controls. Backward regression analysis revealed that the disease activity and the presence of anterior uveitis independently affect IgM anti-TNP levels.
CONCLUSUIONS
Our findings are in accordance with the hypothesis that NAbs contribute to the pathogenesis of autoimmune diseases and provide additional evidence that disturbances in natural autoimmunity may contribute to the as yet unclarified pathogenesis of oligo-JIA.
Topics: Child; Humans; Arthritis, Juvenile; Autoimmunity; Rheumatoid Factor; Uveitis; Uveitis, Anterior; Immunoglobulin M; Immunoglobulin A
PubMed: 37138302
DOI: 10.1186/s12969-023-00823-w -
EBioMedicine Jul 2023The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a...
BACKGROUND
The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk.
METHODS
Data was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n = 17,055), 111 of whom later acquired JIA (ABIS). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed.
FINDINGS
ABIS had higher abundance of Acidaminococcales, Prevotella 9, and Veillonella parvula and lower abundance of Coprococcus, Subdoligranulum, Phascolarctobacterium, Dialister spp., Bifidobacterium breve, Fusicatenibacter saccharivorans, Roseburia intestinalis, and Akkermansia muciniphila (q's < 0.05). Parabacteroides distasonis greatly increased the odds of later contracting JIA (OR = 6.7; 1.81-24.84, p = 0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition.
INTERPRETATION
Microbial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis.
FUNDING
Barndiabetesfonden; Swedish Council for Working Life and Social Research; Swedish Research Council; Östgöta Brandstodsbolag; Medical Research Council of Southeast Sweden; JDRF-Wallenberg Foundation; Linköping.
Topics: Child; Humans; Infant; Arthritis, Juvenile; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Prospective Studies; Genetic Predisposition to Disease
PubMed: 37329576
DOI: 10.1016/j.ebiom.2023.104654 -
Journal of Pediatric Psychology Oct 2019Given the high levels of pain and low rates of treatment adherence in children with juvenile idiopathic arthritis (JIA) and their families, this study sought to examine...
OBJECTIVE
Given the high levels of pain and low rates of treatment adherence in children with juvenile idiopathic arthritis (JIA) and their families, this study sought to examine the relationship between parent pain cognitions (i.e., pain catastrophizing, fear of pain) and treatment adherence, and how barriers to treatment (e.g., forgetting treatments, children resisting injections) may be implicated in this relationship.
METHODS
Parents of children under 18 years of age who have been diagnosed with JIA were recruited to complete an online survey. In total, 221 parents (93% mothers) of children aged 2-17 years (M = 11.10, SD = 4.25) took part, completing questions regarding their pain cognitions, perceived barriers to treatment, and their child's arthritis treatment adherence ability.
RESULTS
Hierarchical regressions demonstrated that both pain cognitions (i.e., pain catastrophizing and fear of pain) were related to a decrease in parent-reported treatment adherence, however, pain catastrophizing was no longer significant when fear of pain was added to the model. The presence of treatment barriers partially mediated the relationship between fear of pain and treatment adherence, above and beyond the alternate model proposed.
CONCLUSION
These results suggest that parent pain catastrophizing and fears of pain are related to a greater difficulty following treatment plans, possibly in part because of barriers parents experience that preclude adherence. Given these findings, the identification and management of parent pain cognitions is critical to improving treatment adherence and outcomes for children with JIA and their families.
Topics: Adolescent; Arthritis, Juvenile; Catastrophization; Child; Child, Preschool; Female; Humans; Male; Pain; Parents; Surveys and Questionnaires; Treatment Adherence and Compliance
PubMed: 31509198
DOI: 10.1093/jpepsy/jsz067 -
Pediatric Rheumatology Online Journal Jun 2021Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders, including all forms of arthritis, which develops in children who are less than 16 years old....
BACKGROUND
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders, including all forms of arthritis, which develops in children who are less than 16 years old. This study aimed to evaluate the clinical and laboratory features of JIA in a single center in Jordan.
METHODS
A retrospective analysis of the electronic medical records of Pediatric patients diagnosed with JIA based on the International League of Associations for Rheumatology (ILAR) criteria during the period from 2015 to 2019 at the Pediatric Rheumatology Clinic in the Queen Rania Children's Hospital. All patients were below the age of 14 years at the time of diagnosis and followed for at least 6 months. Collected data consisted of age, gender, age at initial presentation and diagnosis, JIA subtype, laboratory data, treatment options, and outcome.
RESULTS
A total of 210 patients were included in this cohort (94 males and 116 females) with the mean age at diagnosis and mean age at onset of 5.33 ± 3.40 years and 5.08 ± 3.40 years (range: 7 months - 14 years), respectively. Oligoarticular JIA was the commonest subtype (54.7%), followed by systemic arthritis (17.1%) and polyarticular arthritis (12.3%). ANA was positive in 70 patients (33.6%). Uveitis occurred in 30 (14.2%) patients.
CONCLUSION
To the best of our knowledge, this study on this cohort is the first report on JIA in Jordan, in comparison with other regionally and internationally published reports. Oligoarticular JIA was found to be the most common subtype. For detailed knowledge on JIA characteristics and patterns, a population-based, rather than a single center study, should be conducted in Jordan.
Topics: Adolescent; Arthritis, Juvenile; Child; Child, Preschool; Female; Humans; Infant; Jordan; Male; Retrospective Studies
PubMed: 34118940
DOI: 10.1186/s12969-021-00572-8