Abstract
Objectives
The aim of this study was to identify factors associated with patients’ and parents’ reported satisfaction with JIA care, measured with the juvenile arthritis child and parent ...acceptable symptom state (JA-CASS and JA-PASS, respectively).
Methods
A prospective cohort of 239 JIA patients and 238 parents in a tertiary centre who completed the juvenile arthritis multidimensional assessment report (JAMAR) was analysed cross-sectionally. The primary outcomes were positive JA-CASS and JA-PASS, respectively. Items in the JAMAR, as well as JIA subtype, demographics, and disease activity parameters, were analysed in univariate analysis. A multivariable logistic regression analysis was used to build models explaining the variance of the primary outcome as a dependent variable.
Results
According to the JAMAR, 141 (59.0%) of 239 patients and 149 (62.6%) of 238 parents were satisfied with their or their child’s current condition. For patients, the determinants in the final model were a shorter duration of morning stiffness (P = 0.001), a lower age at disease onset (P = 0.044), a longer disease duration (P = 0.009) and a higher rating of the patient’s well-being measured on a visual analogue scale (VAS) (P = 0.004). For parents, the determinants were the current state of disease activity (current state of persistent activity P = 0.002, relapse P < 0.005), problems at school (P = 0.002) and the items regarding quality of life (QoL) (P = 0.005).
Conclusion
Our data highlight the importance of patients’ and parents’ opinions in the evaluation of disease activity, and support their integration into the shared decision-making in daily clinical practice to improve the quality of medical care.
Dermal fibroblasts are strategically positioned underneath the basal epidermis layer to support keratinocyte proliferation and extracellular matrix production. In inflammatory conditions, these ...fibroblasts produce cytokines and chemokines that promote the chemoattraction of immune cells into the dermis and the hyperplasia of the epidermis, two characteristic hallmarks of psoriasis. However, how dermal fibroblasts specifically contribute to psoriasis development remains largely uncharacterized. In this study, we investigated through which cytokines and signaling pathways dermal fibroblasts contribute to the inflammatory features of psoriatic skin. We show that dermal fibroblasts from lesional psoriatic skin are important producers of inflammatory mediators, including IL-6, CXCL8, and CXCL2. This increased cytokine production was found to be regulated by ZFP36 family members ZFP36, ZFP36L1, and ZFP36L2, RNA-binding proteins with mRNA-degrading properties. In addition, the expression of ZFP36 family proteins was found to be reduced in chronic inflammatory conditions that mimic psoriatic lesional skin. Collectively, these results indicate that dermal fibroblasts are important producers of cytokines in psoriatic skin and that reduced expression of ZFP36 members in psoriasis dermal fibroblasts contributes to their inflammatory phenotype.
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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.
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.
Abstract
Objectives
How the local inflammatory environment regulates epigenetic changes in the context of inflammatory arthritis remains unclear. Here we assessed the transcriptional and active ...enhancer profile of monocytes derived from the inflamed joints of JIA patients, a model well-suited for studying inflammatory arthritis.
Methods
RNA sequencing and H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) were used to analyse the transcriptional and epigenetic profile, respectively, of JIA synovial fluid-derived monocytes.
Results
Synovial-derived monocytes display an activated phenotype, which is regulated on the epigenetic level. IFN signalling-associated genes are increased and epigenetically altered in synovial monocytes, indicating a driving role for IFN in establishing the local inflammatory phenotype. Treatment of synovial monocytes with the Janus-associated kinase (JAK) inhibitor ruxolitinib, which inhibits IFN signalling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype.
Conclusion
This study provides novel insights into epigenetic regulation of inflammatory arthritis patient-derived monocytes and highlights the therapeutic potential of epigenetic modulation for the treatment of inflammatory rheumatic diseases.
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.
To investigate medication prescription patterns among children with JIA, including duration, sequence and reasons for medication discontinuation.
This study is a single-centre, retrospective analysis ...of prospective data from the electronic medical records of JIA patients receiving systemic therapy aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype) and medication prescriptions were extracted and analysed using descriptive statistics, Sankey diagrams and Kaplan-Meier survival methods.
Over a median of 4.2 years follow-up, the 20 different medicines analysed were prescribed as monotherapy (n = 15) or combination therapy (n = 48 unique combinations) among 236 patients. In non-systemic JIA, synthetic DMARDs were prescribed to almost all patients (99.5%), and always included MTX. In contrast, 43.9% of non-systemic JIA patients received a biologic DMARD (mostly adalimumab or etanercept), ranging from 30.9% for oligoarticular persistent ANA-positive JIA, to 90.9% for polyarticular RF-positive JIA. Among systemic JIA, 91.7% received a biologic DMARD (always including anakinra). When analysing medication prescriptions according to their class, 32.6% involved combination therapy. In 56.8% of patients, subsequent treatment lines were initiated after unsuccessful first-line treatment, resulting in 68 unique sequences. Remission was the most common reason for DMARD discontinuation (44.7%), followed by adverse events (28.9%) and ineffectiveness (22.1%).
This paper reveals the complexity of pharmacological treatment in JIA, as indicated by: the variety of mono- and combination therapies prescribed, substantial variation in medication prescriptions between subtypes, most patients receiving two or more treatment lines, and the large number of unique treatment sequences.
Abstract
Objective
JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes ...as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM.
Methods
Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay.
Results
Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01).
Conclusion
Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.
Abstract
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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