Publications by authors named "Sebastiaan J Vastert"

49 Publications

Costs of hospital-associated care for patients with juvenile idiopathic arthritis in the Dutch healthcare system.

Arthritis Care Res (Hoboken) 2021 May 2. Epub 2021 May 2.

Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, Enschede, The Netherlands.

Objective: This study aims to 1) quantify costs of hospital-associated care for juvenile idiopathic arthritis (JIA), 2) provide insights in patient-level variation in costs, and 3) investigate costs over time from the moment of JIA diagnosis. Results are reported for all JIA patients in general and by subtype.

Methods: This study is a single-center, retrospective analysis of prospective data from electronic medical records of children with JIA, aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype), and hospital-based resource use (consultations, medication, radiology procedures, laboratory testing, surgeries, emergency department (ED) visits, hospital stays) were extracted and analyzed. Unit prices were obtained from Dutch reimbursement lists, pharmaceutical list prices, and hospital list prices.

Results: The analysis included 691 patients. Mean total costs of hospital care were €3,784/patient/year, of which €2,103 (55.6%) was attributable to medication. Other costs involved pediatric rheumatologist visits (€633/patient/year, 16.7%), hospital stays (€439/patient/year, 11.6%), other within-hospital specialist visits (€324/patient/year, 8.6%), radiology procedures (€119/patient/year, 3.1%), laboratory tests (€114/patient/year, 3.0%), surgeries (€46/patient/year, 1.2%) and ED visits (€6/patient/year, 0.2%). Mean annual total costs varied between JIA subtypes and between individuals, and were the highest for systemic JIA (€7,772/patient/year). Over the treatment course, costs were the highest in the first month after JIA diagnosis.

Conclusion: Hospital care costs of JIA vary substantially between individuals, between subtypes, and over the treatment course. The highest annual costs were for systemic JIA, primarily attributable to medication (i.e. biologicals). Costs of other hospital-associated care were comparable regardless of subtype.
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http://dx.doi.org/10.1002/acr.24621DOI Listing
May 2021

Serum biomarkers confirming stable remission in inflammatory bowel disease.

Sci Rep 2021 Mar 23;11(1):6690. Epub 2021 Mar 23.

Pediatric Rheumatology and Immunology, University Hospital Muenster, Domagkstr. 3, 48149, Muenster, Germany.

Crohn's disease (CD) and ulcerative colitis (UC) have a chronic-remittent course. Optimal management of inflammatory bowel diseases (IBD) relies on early intervention, treat-to-target strategies and a tight disease control. However, it is challenging to assess the risk of relapses in individual patients. We investigated blood-based biomarkers for the confirmation of disease remission in patients with IBD. We retrospectively analyzed samples of 40 IBD patients (30 UC, 10 CD) enrolled in a tight-control follow-up study. Half of the patients had a flare during follow up. Serum was analyzed for S100A12 as well as S100A8/A9 and for 50 further biomarkers in a bead-based multiplex assay. The concentrations of 9 cytokines/chemokines and S100A8/A9 significantly differed in IBD patients with unstable remission (before flares) when compared to IBD patients with stable remission. Although the number of patients was small, ROC curve analyses revealed a number of biomarkers (IL-1β, IL-1RA, IL-8, IL13, IL-15, IL-21, IL-25, IFN-β, CXCL9, CXCL10, CXCL11, Galectin-1, G-CSF and S100A8/A9) that were elevated in patients with later occurring relapses. While earlier studies on peripheral biomarkers in IBD are limited to only few analytes, our study using a broad screening approach identified serum biomarkers with the potential to indicate unstable disease control in IBD, which may help to steer individual therapies to maintain remission.
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http://dx.doi.org/10.1038/s41598-021-86251-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988138PMC
March 2021

Tissue-Resident Memory T Cells in Chronic Inflammation-Local Cells with Systemic Effects?

Cells 2021 Feb 16;10(2). Epub 2021 Feb 16.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.

Chronic inflammatory diseases such as rheumatoid arthritis (RA), Juvenile Idiopathic Arthritis (JIA), psoriasis, and inflammatory bowel disease (IBD) are characterized by systemic as well as local tissue inflammation, often with a relapsing-remitting course. Tissue-resident memory T cells (T) enter non-lymphoid tissue (NLT) as part of the anamnestic immune response, especially in barrier tissues, and have been proposed to fuel chronic inflammation. T display a distinct gene expression profile, including upregulation of CD69 and downregulation of CD62L, CCR7, and S1PR1. However, not all T are consistent with this profile, and it is now more evident that the T compartment comprises a heterogeneous population, with differences in their function and activation state. Interestingly, the paradigm of T remaining resident in NLT has also been challenged. T cells with T characteristics were identified in both lymph and circulation in murine and human studies, displaying similarities with circulating memory T cells. This suggests that re-activated T are capable of retrograde migration from NLT via differential gene expression, mediating tissue egress and circulation. Circulating 'ex-T' retain a propensity for return to NLT, especially to their tissue of origin. Additionally, memory T cells with T characteristics have been identified in blood from patients with chronic inflammatory disease, leading to the hypothesis that T egress from inflamed tissue as well. The presence of T in both tissue and circulation has important implications for the development of novel therapies targeting chronic inflammation, and circulating 'ex-T' may provide a vital diagnostic tool in the form of biomarkers. This review elaborates on the recent developments in the field of T in the context of chronic inflammatory diseases.
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http://dx.doi.org/10.3390/cells10020409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920248PMC
February 2021

Costs of medication use among patients with juvenile idiopathic arthritis in the Dutch healthcare system.

Expert Rev Pharmacoecon Outcomes Res 2020 Dec 29:1-10. Epub 2020 Dec 29.

Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, Enschede, The Netherlands.

: This study aims to quantify medication costs in juvenile idiopathic arthritis (JIA), based on subtype.: This study is a single-center, retrospective analysis of prospective data from electronic medical records of JIA patients, aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, subtype) and medication use were extracted. Medication use and costs were reported as: 1) mean total annual costs; 2) between-patient heterogeneity in these costs; 3) duration of medication use; and, 4) costs over the treatment course.: The analysis included 691 patients. Mean total medication costs were €2,103/patient/year, including €1,930/patient/year (91.8%) spent on biologicals. Costs varied considerably between subtypes, with polyarticular rheumatoid-factor positive and systemic JIA patients having the highest mean costs (€5,020/patient/year and €4,790/patient/year, respectively). Mean annual medication costs over the patient's treatment course ranged from <€1,000/year (71.1% of patients) to >€11,000/year (2.5% of patients). Etanercept and adalimumab were the most commonly used biologicals. Cost fluctuations over the treatment course were primarily attributable to biological use.: Polyarticular rheumatoid-factor positive and systemic JIA patients had the highest mean total annual medication costs, primarily attributable to biologicals. Costs varied considerably between subtypes, individuals, and over the treatment course.
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http://dx.doi.org/10.1080/14737167.2021.1857241DOI Listing
December 2020

Consensus-based recommendations for the management of juvenile systemic sclerosis.

Rheumatology (Oxford) 2021 Apr;60(4):1651-1658

Department of Woman's and Child's Health, University of Padova, Padua, Italy.

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease.
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http://dx.doi.org/10.1093/rheumatology/keaa584DOI Listing
April 2021

Aiming high: quantifying inflammation in systemic onset juvenile idiopathic arthritis (sJIA), a multi-faceted and complex inflammatory disease.

Rheumatology (Oxford) 2020 11;59(11):3124-3126

Department of Paediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

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http://dx.doi.org/10.1093/rheumatology/keaa394DOI Listing
November 2020

The Patient and Parent Perspective on Methotrexate in Recent Juvenile Idiopathic Arthritis Guidelines: Comment on the Article by Ringold et al.

Arthritis Rheumatol 2020 06 16;72(6):1039-1040. Epub 2020 Apr 16.

Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

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http://dx.doi.org/10.1002/art.41234DOI Listing
June 2020

Tocilizumab as an Effective Treatment Option in Children with Refractory Intermediate and Panuveitis.

Ocul Immunol Inflamm 2021 Jan 14;29(1):21-25. Epub 2020 Feb 14.

Department of Ophthalmology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

: To describe the results of tocilizumab treatment in children with refractory non-anterior uveitis.: A case series of seven children with refractory non-anterior uveitis (onset ≤16 years) with leakage on fluorescein angiogram (FA) were treated with tocilizumab intravenously every 4 weeks (eight mg/kg). Minimum follow-up was 6 months. Reported outcomes are changes in BCVA, central macular thickness (CMT) on OCT image, FA scores, dose of systemic steroids, complications and side effects.: In all patients, there was an improvement of macular edema and capillary leakage on FA. The median FA score decreased from 14 (10-18) at baseline to 8 (2-9) after 6 months of treatment (p = .018). The CMT decreased from 321 (314-384) to 295 (255-312) (p = .043). BCVA improved in five eyes and worsened in one eye due to cataract. No systemic or ocular complications were reported.: Tocilizumab is an effective therapeutic option for reducing disease activity in children with refractory non-anterior uveitis.
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http://dx.doi.org/10.1080/09273948.2020.1712431DOI Listing
January 2021

Anakinra in children and adults with Still's disease.

Rheumatology (Oxford) 2019 11;58(Suppl 6):vi9-vi22

Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.
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http://dx.doi.org/10.1093/rheumatology/kez350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878842PMC
November 2019

Seeking the state of the art in standardized measurement of health care resource use and costs in juvenile idiopathic arthritis: a scoping review.

Pediatr Rheumatol Online J 2019 May 6;17(1):20. Epub 2019 May 6.

Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, P.O. Box 217, 7500, AE, Enschede, the Netherlands.

Background: This study aims to describe current practice in identifying and measuring health care resource use and unit costs in economic evaluations or costing studies of juvenile idiopathic arthritis (JIA).

Methods: A scoping review was conducted (in July 2018) in PubMed and Embase to identify economic evaluations, costing studies, or resource utilization studies focusing on patients with JIA. Only English language peer-reviewed articles reporting primary research were included. Data from all included full-text articles were extracted and analysed to identify the reported health care resource use items. In addition, the data sources used to obtain these resource use and unit costs were identified for all included articles.

Results: Of 1176 unique citations identified by the search, 20 full-text articles were included. These involved 4 full economic evaluations, 5 cost-outcome descriptions, 8 cost descriptions, and 3 articles reporting only resource use. The most commonly reported health care resource use items involved medication (80%), outpatient and inpatient hospital visits (80%), laboratory tests (70%), medical professional visits (70%) and other medical visits (65%). Productivity losses of caregivers were much more often incorporated than (future) productivity losses of patients (i.e. 55% vs. 15%). Family borne costs were not commonly captured (ranging from 15% for school costs to 50% for transportation costs). Resource use was mostly obtained from family self-reported questionnaires. Estimates of unit costs were mostly based on reimbursement claims, administrative data, or literature.

Conclusions: Despite some consistency in commonly included health care resource use items, variability remains in including productivity losses, missed school days and family borne costs. As these items likely substantially influence the full cost impact of JIA, the heterogeneity found between the items reported in the included studies limits the comparability of the results. Therefore, standardization of resource use items and unit costs to be collected is required. This standardization will provide guidance to future research and thereby improve the quality and comparability of economic evaluations or costing studies in JIA and potentially other childhood diseases. This would allow better understanding of the burden of JIA, and to estimate how it varies across health care systems.
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http://dx.doi.org/10.1186/s12969-019-0321-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501309PMC
May 2019

Molecular signature characterisation of different inflammatory phenotypes of systemic juvenile idiopathic arthritis.

Ann Rheum Dis 2019 08 20;78(8):1107-1113. Epub 2019 Apr 20.

Department of Paediatric Rheumatology and Immunology, University of Münster, Münster, Germany

Objectives: The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases.

Methods: Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA ) or polyarticular disease (SJIA ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA , n=45; SJIA , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays.

Results: Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA from SJIA well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA vs SJIA ) and 77% (SJIA vs infection) of all cases.

Conclusions: Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.
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http://dx.doi.org/10.1136/annrheumdis-2019-215051DOI Listing
August 2019

Treatment to Target Using Recombinant Interleukin-1 Receptor Antagonist as First-Line Monotherapy in New-Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five-Year Follow-Up Study.

Arthritis Rheumatol 2019 07 25;71(7):1163-1173. Epub 2019 May 25.

University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

Objective: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage.

Methods: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped.

Results: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL-1Ra was equally effective in systemic JIA patients without arthritis at disease onset.

Conclusion: Treatment to target, starting with first-line, short-course monotherapy with rIL-1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease- and glucocorticoid-related damage in systemic JIA.
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http://dx.doi.org/10.1002/art.40865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617757PMC
July 2019

Consensus-based recommendations for the management of juvenile localised scleroderma.

Ann Rheum Dis 2019 08 2;78(8):1019-1024. Epub 2019 Mar 2.

Klinikum Eilbek, Hamburger Zentrum für Kinder-und Jugendrheumatologie, Hamburg, Germany.

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.
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http://dx.doi.org/10.1136/annrheumdis-2018-214697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691928PMC
August 2019

Restoring T Cell Tolerance, Exploring the Potential of Histone Deacetylase Inhibitors for the Treatment of Juvenile Idiopathic Arthritis.

Front Immunol 2019 7;10:151. Epub 2019 Feb 7.

Laboratory of Translational Immunology, Department of Pediatric Immunology & Rheumatology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands.

Juvenile Idiopathic Arthritis (JIA) is characterized by a loss of immune tolerance. Here, the balance between the activity of effector T (Teff) cells and regulatory T (Treg) cells is disturbed resulting in chronic inflammation in the joints. Presently, therapeutic strategies are predominantly aimed at suppressing immune activation and pro-inflammatory effector mechanisms, ignoring the opportunity to also promote tolerance by boosting the regulatory side of the immune balance. Histone deacetylases (HDACs) can deacetylate both histone and non-histone proteins and have been demonstrated to modulate epigenetic regulation as well as cellular signaling in various cell types. Importantly, HDACs are potent regulators of both Teff cell and Treg cell function and can thus be regarded as attractive therapeutic targets in chronic inflammatory arthritis. HDAC inhibitors (HDACi) have proven therapeutic potential in the cancer field, and are presently being explored for their potential in the treatment of autoimmune diseases. Specific HDACi have already been demonstrated to reduce the secretion of pro-inflammatory cytokines by Teff cells, and promote Treg numbers and suppressive capacity and . In this review, we outline the role of the different classes of HDACs in both Teff cell and Treg cell function. Furthermore, we will review the effect of different HDACi on T cell tolerance and explore their potential as a therapeutic strategy for the treatment of oligoarticular and polyarticular JIA.
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http://dx.doi.org/10.3389/fimmu.2019.00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374297PMC
January 2020

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression.

Pharmaceuticals (Basel) 2019 Jan 8;12(1). Epub 2019 Jan 8.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Faculty of Science, Universities 99, 3584 CG Utrecht, The Netherlands.

Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate⁻cyclohydrolase-1 (GTP⁻CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4). These compounds play a crucial role in the synthesis and metabolism of neurotransmitters. The aim of our study was to reveal whether inflammation affects both the GTP-CH1 and IDO pathway in JIA patients. Serum samples were collected from twenty-four JIA patients. In these samples, the concentrations of tryptophan (TRP), kynurenine (KYN), tyrosine (TYR), neopterin, and phenylalanine (PHE) were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine, and tyrosine. Neopterin and phenylalanine were quantified by ELISA. The KYN/TRP ratio was measured as an index of IDO activity, while the PHE/TYR ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity. JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both KYN/TRP and PHE/TYR and lower tryptophan levels than clinically inactive patients. Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 but decreases the efficacy of the co-factor BH4. In the future, animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor BH4 lower the levels of the brain neurotransmitters glutamate, noradrenaline, dopamine, serotonin, and melatonin, and consequently, whether they may affect fatigue, cognition, anxiety, and depression. Understanding of these complex neuroimmune interactions provides new possibilities for Pharma-Food interventions to improve the quality of life of patients suffering from chronic inflammation.
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http://dx.doi.org/10.3390/ph12010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469185PMC
January 2019

Microbiome Analytics of the Gut Microbiota in Patients With Juvenile Idiopathic Arthritis: A Longitudinal Observational Cohort Study.

Arthritis Rheumatol 2019 06 29;71(6):1000-1010. Epub 2019 Apr 29.

Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Objective: To assess the composition of gut microbiota in Italian and Dutch patients with juvenile idiopathic arthritis (JIA) at baseline, with inactive disease, and with persistent activity compared to healthy controls.

Methods: In a multicenter, prospective, observational cohort study, fecal samples were collected at baseline from 78 Italian and 21 Dutch treatment-naive JIA patients with <6 months of disease duration and compared to 107 geographically matched samples from healthy children. Forty-four follow-up samples from patients with inactive disease and 25 follow-up samples from patients with persistent activity were analyzed. Gut microbiota composition was determined by 16S ribosomal RNA-based metagenomics. Alpha- and β-diversity were computed, and log ratios of relative abundance were compared between patients and healthy controls using random forest models and logistic regression.

Results: Baseline samples from Italian patients showed reduced richness compared to healthy controls (P < 0.001). Random forest models distinguished between Italian patient baseline samples and healthy controls and suggested differences between Dutch patient samples and healthy controls (areas under the curve >0.99 and 0.71, respectively). The operational taxonomic units (OTUs) of Erysipelotrichaceae (increased in patients), Allobaculum (decreased in patients), and Faecalibacterium prausnitzii (increased in patients) showed different relative abundance in Italian patient baseline samples compared to controls after controlling for multiple comparisons. Some OTUs differed between Dutch patient samples and healthy controls, but no evidence remained after controlling for multiple comparisons. No differences were found in paired analysis between Italian patient baseline and inactive disease samples.

Conclusion: Our findings show evidence for dysbiosis in JIA patients. Only patient/control status, age, and geographic origin appear to be drivers of the microbiota profiles, regardless of disease activity stage, inflammation, and markers of autoimmunity.
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http://dx.doi.org/10.1002/art.40827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593809PMC
June 2019

Dutch juvenile idiopathic arthritis patients, carers and clinicians create a research agenda together following the James Lind Alliance method: a study protocol.

Pediatr Rheumatol Online J 2018 Sep 15;16(1):57. Epub 2018 Sep 15.

Pediatric Rheumatology and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands.

Background: Research on Juvenile Idiopathic Arthritis (JIA) should support patients, caregivers/parents (carers) and clinicians to make important decisions in the consulting room and eventually to improve the lives of patients with JIA. Thus far these end-users of JIA-research have rarely been involved in the prioritisation of future research.

Main Body: Dutch organisations of patients, carers and clinicians will collaboratively develop a research agenda for JIA, following the James Lind Alliance (JLA) methodology. In a 'Priority Setting Partnership' (PSP), they will gradually establish a top 10 list of the most important unanswered research questions for JIA. In this process the input from clinicians, patients and their carers will be equally valued. Additionally, focus groups will be organised to involve young people with JIA. The involvement of all contributors will be monitored and evaluated. In this manner, the project will contribute to the growing body of literature on how to involve young people in agenda setting in a meaningful way.

Conclusion: A JIA research agenda established through the JLA method and thus co-created by patients, carers and clinicians will inform researchers and research funders about the most important research questions for JIA. This will lead to research that really matters.
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http://dx.doi.org/10.1186/s12969-018-0276-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139167PMC
September 2018

Prediction of inactive disease in juvenile idiopathic arthritis: a multicentre observational cohort study.

Rheumatology (Oxford) 2018 10;57(10):1752-1760

Paediatric Rheumatology, Istituto Giannina Gaslini, Genoa, Italy.

Objectives: To predict the occurrence of inactive disease in JIA in the first 2 years of disease.

Methods: An inception cohort of 152 treatment-naïve JIA patients with disease duration <6 months was analysed. Potential predictors were baseline clinical variables, joint US, gut microbiota composition and a panel of inflammation-related compounds in blood plasma. Various algorithms were employed to predict inactive disease according to Wallace criteria at 6-month intervals in the first 2 years. Performance of the models was evaluated using the split-cohort technique. The cohort was analysed in its entirety, and separate models were developed for oligoarticular patients, polyarticular RF negative patients and ANA positive patients.

Results: All models analysing the cohort as a whole showed poor performance in test data [area under the curve (AUC): <0.65]. The subgroup models performed better. Inactive disease was predicted by lower baseline juvenile arthritis DAS (JADAS)-71 and lower relative abundance of the operational taxonomic unit Mogibacteriaceae for oligoarticular patients (AUC in test data: 0.69); shorter duration of morning stiffness, higher haemoglobin and lower CXCL-9 levels at baseline for polyarticular RF negative patients (AUC in test data: 0.69); and shorter duration of morning stiffness and higher baseline haemoglobin for ANA positive patients (AUC in test data: 0.72).

Conclusion: Inactive disease could not be predicted with satisfactory accuracy in the whole cohort, likely due to disease heterogeneity. Interesting predictors were found in more homogeneous subgroups. These need to be validated in future studies.
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http://dx.doi.org/10.1093/rheumatology/key148DOI Listing
October 2018

Treating juvenile idiopathic arthritis to target: recommendations of an international task force.

Ann Rheum Dis 2018 06 11;77(6):819-828. Epub 2018 Apr 11.

Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht and University of Utrecht, Utrecht, The Netherlands.

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA.
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http://dx.doi.org/10.1136/annrheumdis-2018-213030DOI Listing
June 2018

Editorial: Toward Personalized Treatment for Systemic Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2018 08 29;70(8):1172-1174. Epub 2018 Jun 29.

Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/art.40501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105394PMC
August 2018

The safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade: an international survey.

Pediatr Rheumatol Online J 2018 Mar 21;16(1):19. Epub 2018 Mar 21.

Department of General Pediatrics, University Medical Center Utrecht, Room KE 04 133 1, PO-Box 85090, 3508, AB Utrecht, The Netherlands.

Background: Withholding live-attenuated vaccines in patients using interleukin (IL)-1 or IL-6 blocking agents is recommended by guidelines for both pediatric and adult rheumatic diseases, since there is a risk of infection in an immune suppressed host. However, this has never been studied. This retrospective, multicenter survey aimed to evaluate the safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade.

Methods: We contacted physicians involved in the treatment of autoinflammatory diseases to investigate potential cases. Patients were included if a live-attenuated vaccine had been administered while they were on IL-1 or IL-6 blockade.

Results: Seventeen patients were included in this survey (7 systemic juvenile idiopathic arthritis (sJIA), 5 cryopyrin associated periodic syndrome (CAPS), 4 mevalonate kinase deficiency (MKD) and 1 familial Mediterranean fever (FMF). Three patients experienced an adverse event, of which two were serious adverse events (a varicella zoster infection after varicella zoster booster vaccination, and a pneumonia after MMR booster). One additional patient had diarrhea after oral polio vaccine. Further, seven patients experienced a flare of their disease, which were generally mild. Eight patients did not experience an adverse event or a flare.

Conclusion: We have described a case series of seventeen patients who received a live-attenuated vaccine while using IL-1 or IL-6 blocking medication. The findings of this survey are not a reason to adapt the existing guidelines. Prospective trials are needed in order to acquire more evidence about the safety and efficacy before considering adaptation of guidelines.
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http://dx.doi.org/10.1186/s12969-018-0235-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863478PMC
March 2018

Contradictory and weak evidence on the effectiveness of anti-emetics for MTX-intolerance in JIA-patients.

Pediatr Rheumatol Online J 2018 02 15;16(1):13. Epub 2018 Feb 15.

Department of Pediatric Rheumatology and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Room KC.03.063.0, P.O. box 85090, 3508 AB, Utrecht, Netherlands.

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http://dx.doi.org/10.1186/s12969-018-0229-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815175PMC
February 2018

Reversal of Sepsis-Like Features of Neutrophils by Interleukin-1 Blockade in Patients With Systemic-Onset Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2018 06 7;70(6):943-956. Epub 2018 May 7.

University Medical Center Utrecht, Wilhelmina Children's Hospital and Utrecht University, Utrecht, The Netherlands.

Objective: Neutrophils are the most abundant innate immune cells in the blood, but little is known about their role in (acquired) chronic autoinflammatory diseases. This study was undertaken to investigate the role of neutrophils in systemic-onset juvenile idiopathic arthritis (JIA), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation.

Methods: Fifty patients with systemic-onset JIA who were receiving treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) were analyzed at disease onset and during remission. RNA sequencing was performed on fluorescence-activated cell-sorted neutrophils from 3 patients with active systemic-onset JIA and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (ROS), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic-onset JIA and 15 healthy controls.

Results: Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of rIL-1Ra therapy. RNA-sequencing analysis revealed a substantial up-regulation of inflammatory processes in neutrophils from patients with active systemic-onset JIA, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic-onset JIA displayed a primed phenotype that was characterized by increased ROS production, CD62L shedding, and secretory vesicle degranulation, which was reversed by rIL-1Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to rIL-1Ra, whereas patients with symptoms for >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1Ra. In vitro, rIL-1Ra antagonized the priming effect of IL-1β on neutrophils from healthy subjects.

Conclusion: These results strongly support the notion that neutrophils play an important role in systemic-onset JIA, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic-onset JIA are both susceptible to IL-1 blockade.
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http://dx.doi.org/10.1002/art.40442DOI Listing
June 2018

Patient's experiences with the care for juvenile idiopathic arthritis across Europe.

Pediatr Rheumatol Online J 2018 Feb 8;16(1):10. Epub 2018 Feb 8.

Paediatric Rheumatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Room KC.03.063.0, P.O. box 85090, 3508, AB, Utrecht, The Netherlands.

Background: To assess the views of juvenile idiopathic arthritis (JIA) patients and their parents on the care and treatment they receive in referral pediatric rheumatology centers throughout Europe.

Methods: In a collaboration between physicians and patient associations, a questionnaire was developed, covering various domains of JIA care, including demographics, diagnosis, referrals to various health care professionals, access to pain and fatigue management and support groups, information they received about the disease and awareness of and participation in research. The questionnaire was translated and distributed by parent associations and pediatric rheumatologists in 25 countries, 22 of which were European. After completion the replies were entered on the PRINTO website. Replies could either be entered directly by parents on the website or on paper. In these cases, the replies were scanned and emailed by local hospital staff to Utrecht where they were entered by I.R. in the database.

Results: The survey was completed by 622 parents in 23 countries. The majority (66.7%) of patients were female, with median age 10-11 years at the completion of the questionnaire. Frequencies of self-reported JIA categories corresponded to literature. Some patients had never been referred to the ophthalmologist (22.8%) or physiotherapist (31.7%). Low rates of referral or access to fatigue (3.5%) or pain management teams (10.0%), age appropriate disease education (11.3%), special rehabilitation (13.7%) and support groups (20.1%) were observed. Many patients indicated they did not have contact details for urgent advice (35.9%) and did not receive information about immunizations (43.2%), research (55.6%) existence of transition of care clinics (89,2%) or financial support (89.7%). While on immunosuppressive drugs, about one half of patients did not receive information about immunizations, travelling, possible infections or how to deal with chickenpox or shingles.

Conclusions: Low rates of referral to health care professionals may be due to children whose illness is well managed and who do not need additional support or information. Improvements are needed, especially in the areas of supportive care and information patients receive. It is also important to improve doctor patient communication between visits. Physicians can be instrumental in the setting up of support groups and increasing patients' awareness of existing support. Suggestions are given to convey crucial pieces of information structurally and repeatedly to ensure, among other things, compliance.
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http://dx.doi.org/10.1186/s12969-018-0226-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806356PMC
February 2018

Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative.

Ann Rheum Dis 2018 03 11;77(3):319-327. Epub 2017 Oct 11.

Division of Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tübingen, Germany.

Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases.
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http://dx.doi.org/10.1136/annrheumdis-2017-211904DOI Listing
March 2018

Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential.

Arthritis Rheumatol 2017 10;69(10):1925-1936

Laboratory of Translational Immunology, Wilhelmina Children's Hospital and University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1002/art.40194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659109PMC
October 2017

European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative.

Ann Rheum Dis 2017 Oct 4;76(10):1637-1641. Epub 2017 May 4.

Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK.

Antiphospholipid syndrome (APS) is rare in children, and evidence-based guidelines are sparse. Consequently, management is mostly based on observational studies and physician's experience, and treatment regimens differ widely. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative was launched to develop diagnostic and management regimens for children and young adults with rheumatic diseases. Here, we developed evidence-based recommendations for diagnosis and treatment of paediatric APS. Evidence-based recommendations were developed using the European League Against Rheumatism standard operating procedure. Following a detailed systematic review of the literature, a committee of paediatric rheumatologists and representation of paediatric haematology with expertise in paediatric APS developed recommendations. The literature review yielded 1473 articles, of which 15 were valid and relevant. In total, four recommendations for diagnosis and eight for treatment of paediatric APS (including paediatric Catastrophic Antiphospholipid Syndrome) were accepted. Additionally, two recommendations for children born to mothers with APS were accepted. It was agreed that new classification criteria for paediatric APS are necessary, and APS in association with childhood-onset systemic lupus erythematosus should be identified by performing antiphospholipid antibody screening. Treatment recommendations included prevention of thrombotic events, and treatment recommendations for venous and/or arterial thrombotic events. Notably, due to the paucity of studies on paediatric APS, level of evidence and strength of the recommendations is relatively low. The SHARE initiative provides international, evidence-based recommendations for diagnosis and treatment for paediatric APS, facilitating improvement and uniformity of care.
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http://dx.doi.org/10.1136/annrheumdis-2016-211001DOI Listing
October 2017

The human microbiome and juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2016 Sep 20;14(1):55. Epub 2016 Sep 20.

Department of Paediatric Infectious Diseases, Wilhelmina Children's Hospital, Lundlaan 6, 3584 EA, Utrecht, The Netherlands.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The pathogenesis of JIA is thought to be the result of a combination of host genetic and environmental triggers. However, the precise factors that determine one's susceptibility to JIA remain to be unravelled. The microbiome has received increasing attention as a potential contributing factor to the development of a wide array of immune-mediated diseases, including inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis. Also in JIA, there is accumulating evidence that the composition of the microbiome is different from healthy individuals. A growing body of evidence indeed suggests that, among others, the microbiome may influence the development of the immune system, the integrity of the intestinal mucosal barrier, and the differentiation of T cell subsets. In turn, this might lead to dysregulation of the immune system, thereby possibly playing a role in the development of JIA. The potential to manipulate the microbiome, for example by faecal microbial transplantation, might then offer perspectives for future therapeutic interventions. Before we can think of such interventions, we need to first obtain a deeper understanding of the cause and effect relationship between JIA and the microbiome. In this review, we discuss the existing evidence for the involvement of the microbiome in JIA pathogenesis and explore the potential mechanisms through which the microbiome may influence the development of autoimmunity in general and JIA specifically.
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http://dx.doi.org/10.1186/s12969-016-0114-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028952PMC
September 2016

Autoimmune disease-associated gene expression is reduced by BET-inhibition.

Genom Data 2016 Mar 7;7:14-7. Epub 2015 Nov 7.

Dept. of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands; Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, The Netherlands.

For many autoimmune diseases, the underlying mechanism is still unknown. In order to get more insight into the etiology of autoimmune diseases, we recently published a study were we performed epigenetic profiling and RNA sequencing on CD4(+)CD45RO(+) T cells derived from the site of inflammation of Juvenile Idiopathic Arthritis (JIA) patients and compared this with healthy controls [1]. In this "Data in Brief", we focus on the analysis of our RNA sequencing data reported in this study, of which the raw and processed files can be found in GEO under GSE71595. We provide a detailed description of the downstream analysis, quality controls, and different analysis methods or techniques that validate the results obtained with RNA-sequencing.
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http://dx.doi.org/10.1016/j.gdata.2015.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778599PMC
March 2016

Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression.

Cell Rep 2015 Sep 17;12(12):1986-96. Epub 2015 Sep 17.

Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands; Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands. Electronic address:

The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.
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http://dx.doi.org/10.1016/j.celrep.2015.08.046DOI Listing
September 2015