Autoimmune response to transthyretin in juvenile idiopathic arthritis.
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ABSTRACT:
SUBMITTER: Clement CC
PROVIDER: S-EPMC4784708 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35-45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.
| S-EPMC4369651 | biostudies-literature
Project description:Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.
| S-EPMC4848803 | biostudies-other
Project description:Background: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritis of childhood, characterized by various clinical phenotypes associated with variable prognosis. Significant progress has been achieved with the use of biologic treatments, which specifically block pro-inflammatory molecules involved in the disease pathogenesis. The most commonly used biologics in JIA are monoclonal antibodies and recombinant proteins targeting interleukins 1 (IL-1) and 6 (IL-6), and tumor necrosis factor α (TNF-α). Several biomarkers have been investigated in JIA. Aims: To assess the level of evidence available regarding the role of biomarkers in JIA related to guiding clinical and therapeutic decisions, providing disease prognostic information, facilitating disease activity monitoring and assessing biologic treatment response in JIA, as well as propose new strategies for biologic therapy-related biomarker use in JIA. Methods: We searched PubMed for relevant literature using predefined key words corresponding to several categories of biomarkers to assess their role in predicting and assessing biologic treatment response and clinical remission in JIA. Results: We reviewed serological, cellular, genetic, transcriptomic and imaging biomarkers, to identify candidates that are both well-established and widely used, as well as newly investigated in JIA on biologic therapy. We evaluated their role in management of JIA as well as identified the unmet needs for new biomarker discovery and better clinical applications. Conclusion: Although there are no ideal biomarkers in JIA, we identified serological biomarkers with potential clinical utility. We propose strategies of combining biomarkers of response to biologics in JIA, as well as routine implementation of clinically acceptable imaging biomarkers for improved disease assessment performance.
| S-EPMC7884612 | biostudies-literature
Project description:BACKGROUND:Many autoimmune diseases share common pathogenic mechanisms, cytokine pathways and systemic inflammatory cascades; however, large studies quantifying the co-existence of autoimmune diseases in patients with juvenile idiopathic arthritis (JIA) have not been conducted. METHODS:We performed a cross-sectional study using two United States administrative healthcare claims databases (Truven Health MarketScan® Commercial Database and IMS PharMetrics database) to screen for the prevalence of multiple autoimmune diseases in patients with JIA and in a control group with attention deficit hyperactivity disorder (ADHD). Patients with a diagnosis code for JIA or ADHD between January 1, 2006 and September 30, 2017 were separated into two age cohorts (<?18 and???18?years) and matched (maximum 1:5) based on age, sex, number of medical encounters, and calendar year of diagnosis. The prevalence rates of 30 pre-specified autoimmune diseases during the 12-month periods before and after diagnosis were compared. RESULTS:Overall, 29,215 patients with JIA and 134,625 matched control patients with ADHD were evaluated. Among patients in the MarketScan database, 28/30 autoimmune diseases were more prevalent in patients with JIA aged <?18?years and 29/30 were more prevalent in patients aged ? 18?years when compared with a matched cohort of patients with ADHD. In the PharMetrics database, 29/30 and 30/30 autoimmune diseases were more prevalent in patients with JIA aged <?18 and???18?years, respectively, compared with a matched cohort of patients with ADHD. Among patients with JIA aged <?18?years, the greatest odds ratios (ORs) were seen for Sjögren's syndrome/sicca syndrome and uveitis. Among patients aged ? 18?years in the MarketScan database, the greatest ORs were recorded for uveitis. Data from the PharMetrics database indicated that the greatest ORs were for uveitis and chronic glomerulonephritis. CONCLUSIONS:Patients with JIA are more likely to have concurrent autoimmune diseases than matched patients with ADHD. Having an awareness of the co-existence of autoimmune diseases among patients with JIA may play an important role in patient management, treatment decisions, and outcomes. TRIAL REGISTRATION:Not applicable.
| S-EPMC7275412 | biostudies-literature
Project description:ObjectiveTo explore the shared gene signatures and potential molecular mechanisms of polyarticular juvenile idiopathic arthritis (pJIA) and autoimmune uveitis (AU).MethodThe microarray data of pJIA and AU from the Gene Expression Omnibus (GEO) database were downloaded and analyzed. The GEO2R tool was used to identify the shared differentially expressed genes (DEGs) and genes of extracellular proteins were identified among them. Then, weighted gene co-expression network analysis (WGCNA) was used to identify the shared immune-related genes (IRGs) related to pJIA and AU. Moreover, the shared transcription factors (TFs) and microRNAs (miRNAs) in pJIA and AU were acquired by comparing data from HumanTFDB, hTFtarget, GTRD, HMDD, and miRTarBase. Finally, Metascape and g: Profiler were used to carry out function enrichment analyses of previously identified gene sets.ResultsWe found 40 up-regulated and 15 down-regulated shared DEGs via GEO2R. Then 24 shared IRGs in positivity-related modules, and 18 shared IRGs in negatively-related modules were found after WGCNA. After that, 3 shared TFs (ARID1A, SMARCC2, SON) were screened. And the constructed TFs-shared DEGs network indicates a central role of ARID1A. Furthermore, hsa-miR-146 was found important in both diseases. The gene sets enrichment analyses suggested up-regulated shared DEGs, TFs targeted shared DEGs, and IRGs positivity-correlated with both diseases mainly enriched in neutrophil degranulation process, IL-4, IL-13, and cytokine signaling pathways. The IRGs negatively correlated with pJIA and AU mainly influence functions of the natural killer cell, cytotoxicity, and glomerular mesangial cell proliferation. The down-regulated shared DEGs and TFs targeted shared DEGs did not show particular functional enrichment.ConclusionOur study fully demonstrated the flexibility and complexity of the immune system disorders involved in pJIA and AU. Neutrophil degranulation may be considered the shared pathogenic mechanism, and the roles of ARID1A and MiR-146a are worthy of further in-depth study. Other than that, the importance of periodic inspection of kidney function is also noteworthy.
| S-EPMC10030950 | biostudies-literature
Project description:To describe recent evidence from the literature pertaining to juvenile idiopathic arthritis (JIA)-associated uveitis.Uveitis is most common in extended oligoarticular JIA. A significant number of patients already have ocular complications at time of diagnosis of uveitis. Risk factors for complications include either abnormally high or low intraocular pressure, posterior synechiae, male sex, temporal proximity to diagnosis of arthritis and topical corticosteroid use. Use of immunosuppressive agents significantly reduces ocular complications. Aggressive perioperative control of intraocular inflammation is necessary for successful cataract surgery with lens implantation. Controlled clinical trials are under way to assess the efficacy of biologic agents in JIA-associated uveitis. Long-term safety, however, is still unknown.JIA-associated uveitis carries significant ocular morbidity that lasts well into adulthood. Treatment with immunosuppressive agents can reduce the risk of ocular complications. Biologic agents hold promise in the treatment of JIA-associated uveitis, but require long-term data to assess their safety.
| S-EPMC3089768 | biostudies-literature
Project description:Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease. The development of associated uveitis represents a significant risk for serious complications, including permanent loss of vision. Initiation of early treatment is important for controlling JIA-uveitis, but the disease can appear asymptomatically, making frequent screening procedures necessary for patients at risk. As our understanding of pathogenic drivers is currently incomplete, it is difficult to assess which JIA patients are at risk of developing uveitis. Identification of specific risk factors for JIA-associated uveitis is an important field of research, and in this review, we highlight the genomic, transcriptomic, and proteomic factors identified as potential uveitis risk factors in JIA, and discuss therapeutic strategies.
| S-EPMC8393258 | biostudies-literature
Project description:BackgroundHaptoglobin (Hp), a liver derived acute phase inflammatory protein (APP), has scarcely been studied in juvenile idiopathic arthritis (JIA). Hp can occur in blood as two isoforms (Hp1 and Hp2) in precursor and mature forms. Routine clinical chemistry immunoturbidimetry does not discern these forms. It is unknown how different forms relate to disease activity in JIA. Our aims were to determine allele frequency and plasma concentrations of different Hp forms at higher versus lower JIA disease activity and compare to other APPs.MethodsPlasma from JIA (n = 77) and healthy (n = 42) children were analyzed for apparent Hp allelic frequency and densitometric concentrations of alpha forms by Western blot (WB). Polymerase chain reaction (PCR) (buffy coat) was performed in a subset to estimate conformity with genetics. At higher versus lower juvenile arthritis disease activity score (JADAS27) (which includes erythrocyte sedimentation rate (ESR)), total mature Hp concentration from WB was compared and correlated against immunoturbidimetry and total protein, albumin, serum amyloid A (SAA) and C-reactive protein (CRP).ResultsAt 300-fold dilution needed to study mature forms in Western blot, precursors were undetectable. Hp2 contributed most signal in most samples. Hp allele frequency was similar in JIA and controls. Both mature forms, taken separately or by sum, declined following treatment, but remained above concentrations of healthy controls, even in a remission subset that achieved JADAS27 < 1. Densitometry correlated with immunoturbidimetry. Hp concentrations correlated with JADAS27, albumin (negatively), CRP and SAA with immunoturbidimetric method correlating strongest to JADAS27 (Spearman R ~ 0.6, p < 0.0001).ConclusionHp allele frequency in JIA is similar to the general population, indicating that children with JIA should have the same possibility as in healthy children to produce preHp2 (zonulin), thought to increase intestinal permeability. Circulating Hp concentrations largely parallel other APPs and ESR; none of these measures correlate very strongly to JADAS27 score but Hp can be measured from capillary sampling which is impossible with ESR.
| S-EPMC9753416 | biostudies-literature
Project description:Secondary thrombotic microangiopathies are associated with several underlying conditions, with most of them being resolved after the treatment of background disease. Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathy presenting with anemia, thrombocytopenia, and neurological deficits, occurring most often in various autoimmune diseases due to inhibition of ADAMTS13 by autoantibodies, as well as in pregnant women with or without an autoimmune substrate. In this article, we report two newly diagnosed TTP cases, who have not been published so far. The first is a 27-year-old woman with a history of polyarticular rheumatoid factor negative juvenile idiopathic arthritis, who presented with thrombocytopenia, anemia, schistocytes on blood smear, headache, and active arthritis. Originally she was treated successfully with plasma exchange, intravenous prednisone, and vincristine, and a few months after the TTP episode, she was commenced on rituximab, resulting in remission of primary disease and no relapse of TTP. The second case refers to a 29-year-old pregnant woman complaining of dizziness and fatigue with microangiopathic hemolytic anemia. She was treated with plasma exchanges, intravenous prednisolone, and INN human normal immunoglobulin with full remission of the TTP episode. Six and half years later, she was diagnosed with multiple sclerosis and was commenced on interferon beta-1 alpha, with no recurrent episode of TTP. These cases broaden the spectrum of autoimmune disorders manifested or complicated clinically by TTP. Furthermore, biological agents such as rituximab appear to be an effective treatment option for refractory cases of TTP related to systemic rheumatic disease, indicating an alternative therapeutic solution in persistent cases of this disorder.
| S-EPMC5522843 | biostudies-other
Project description:ObjectiveAround one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response.MethodsS100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded.ResultsBaseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133-440 ng/ml] and MTX (median 220, IQR 100-440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125-615) ng/ml versus 150 (IQR 87-233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150-624) ng/ml versus 151 (IQR 83-201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10.ConclusionResponders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.
| S-EPMC5880729 | biostudies-literature