Childhood-onset systemic lupus erythematosus: characteristics and the prospect of glucocorticoid pulse therapy.

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease that results in significant damage and often needs more aggressive treatment. Compared to adult-onset SLE, cSLE has a stronger genetic background and more prevalent elevated type I Interferon expression. The management of cSLE is more challenging because the disease itself and treatment can affect physical, psychological and emotional growth and development.

Extracutaneous involvement is common and associated with prolonged disease activity and greater impact in juvenile localized scleroderma.

Objective: The aim of this study was to evaluate factors associated with extracutaneous involvement (ECI) in juvenile localized scleroderma (jLS).

Methods: A prospective, multicentre, 6-month observational study was performed. The data collected included disease features, global assessments, and subject symptoms.

Mapping systemic lupus erythematosus heterogeneity at the single-cell level.

Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.

Developing comparative effectiveness studies for a rare, understudied pediatric disease: lessons learned from the CARRA juvenile localized scleroderma consensus treatment plan pilot study.

Background: We designed and initiated a pilot comparative effectiveness study for juvenile localized scleroderma (jLS), for which there is limited evidence on best therapy. We evaluated the process we used, in relation to the specific protocol and to the general task of identifying strategies for implementing studies in rare pediatric diseases.

Methods: This was a prospective, multi-center, observational cohort study of 50 jLS patients initiating treatment, designed and conducted by the jLS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) from 2012 to 2015.

A CD4 T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate.

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE). Follicular helper T cells (T cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers.

New Features for Measuring Disease Activity in Pediatric Localized Scleroderma.

Objective: To identify clinical features that define disease activity in pediatric localized scleroderma (LS), and determine their specificity and importance.

Methods: We conducted a multicenter prospective study of patients with active and inactive LS skin lesions. A standardized evaluation of a single designated study lesion per subject was performed at 3 visits.

Biologics for childhood systemic vasculitis.

Recent advances have allowed better understanding of vasculitis pathogenesis and led to more targeted therapies. Two pivotal randomized controlled trials, RITUXVAS and rituximab in ANCA-associated vasculitis (RAVE), provide high-quality evidence demonstrating rituximab (RTX) is efficacious in inducing remission in adult ANCA-associated vasculitis (AAV) patients compared with cyclophosphamide (CYC). RAVE also demonstrated superiority of RTX to oral CYC for induction of remission in relapsing disease.

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.

Age and fecal microbial strain-specific differences in patients with spondyloarthritis.

Background: Prior studies have demonstrated abnormalities in the composition of the gastrointestinal microbiota in pediatric and adult patients with spondyloarthritis (SpA). In particular, diminished fecal abundance of Faecalibacterium prausnitzii and abnormalities in both directions in the abundance of the Bacteroides genus have been identified.

Methods: We obtained fecal specimens from 30 children with treatment-naïve enthesitis-related arthritis (ERA) and 19 healthy controls, as well as specimens from 11 adult patients with longstanding SpA and 10 adult healthy controls.

A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis.

The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets.

Genome-Wide Association Meta-Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci.

Objective: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes.

Pilot study comparing the Childhood Arthritis & Rheumatology Research Alliance (CARRA) systemic Juvenile Idiopathic Arthritis Consensus Treatment Plans.

Objectives: To assess the feasibility of studying the comparative effectiveness of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans (CTPs) for systemic Juvenile Idiopathic Arthritis (JIA) using an observational registry.

Methods: Untreated systemic JIA patients enrolled in the CARRA Registry were begun on one of 4 CTPs chosen by the treating physician and patient/family (glucocorticoid [GC] alone; methotrexate [MTX] ± GC; IL1 inhibitor [IL1i] ± GC; IL6 inhibitor [IL6i] ± GC). The primary outcome of clinical inactive disease (CID) without current GC use was assessed at 9 months.

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

Objective: To develop response criteria for juvenile dermatomyositis (DM).

Methods: We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial.

Paediatric systemic lupus erythematosus: insights from translational research.

Investigations in paediatric SLE contributed significantly to the discovery of the association of type I IFNs with lupus and underscored the potential application of this knowledge by informing the use of glucocorticoid therapy. Recent, promising research reveals biomarkers that may yield more focused clinical monitoring and assessment of response to treatment. This article reviews unique features of paediatric SLE and details important developments in paediatric lupus research.

Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting : Toronto, Canada. 14-17 April 2016.

P1 Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis Lampros Fotis, Nur Shaikh, Kevin Baszis, Anthony French, Phillip Tarr P2 Oral health and anti-citrullinated peptide antibodies (ACPA) in juvenile idiopathic arthritis Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newsom, Anne Stevens P3 Novel autoantigens for endothelial cell antibodies in pediatric rheumatic diseases identified by proteomics Rie Karasawa, Mayumi Tamaki, Megumi Tanaka, Toshiko Sato, Kazuo Yudoh, James N. Jarvis P4 Transcriptional profiling reveals monocyte signature associated with JIA patient poor response to methotrexate Halima Moncrieffe, Mark F. Bennett, Monica Tsoras, Lorie Luyrink, Huan Xu, Sampath Prahalad, Paula Morris, Jason Dare, Peter A.

Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.

Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage.

Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA.

Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility.

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.

Methods: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG.

Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years.

Objective: The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease-modifying antirheumatic drugs were previously established in a phase III study that included a 4-month open-label lead-in period, a 6-month double-blind withdrawal period, and a long-term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient-reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup.

Methods: Patients enrolled in the phase III trial could enter the open-label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double-blind period.