Safety, immunogenicity and efficacy of the Shingrix vaccine in immunocompromised varicella zoster virus naïve pediatric patients.

Background: Pediatric patients with autoimmune and inflammatory diseases often require immunosuppressive therapy, which increases their susceptibility to infections, including varicella-zoster virus (VZV). While the live attenuated varicella vaccine is contraindicated in most immunocompromised children, the recombinant subunit vaccine, Shingrix, may offer an alternative preventive strategy. However, data on its safety, immunogenicity, and efficacy in pediatric VZV-naïve patients remain limited.

LIMK1 variants are associated with divergent endocrinological phenotypes and altered exocytosis dynamics.

LIM kinase 1 (LIMK1) plays a pivotal role in dynamic actin remodeling through phosphorylation of cofilin, thereby regulating exocytosis. We report two individuals harboring variants with dissimilar phenotypes: one exhibited epileptic encephalopathy and developmental delay, while the other showed common variable immune deficiency and glucose dysregulation. We suspected that the divergent phenotypic features arose from opposing effects on LIMK1 activity.

When to address fatigue in juvenile idiopathic arthritis during clinical visits based on the JAMAR.

Objectives: Fatigue is a prevalent but overlooked issue among patients with Juvenile Idiopathic Arthritis (JIA) in clinical practice. The internationally widely used Juvenile Arthritis Multidimensional Assessment Report (JAMAR) does not include items on fatigue. We evaluated whether items from its Quality of Life (QoL) section could be used as proxy measurement for fatigue, prompting practitioners to address issues with fatigue during a clinical visit.

Impact of Interleukin-1 Blockade on the Development of Macrophage Activation Syndrome in Still Disease: Incidence and Diagnostic Validity of the EULAR/ACR/PRINTO 2016 MAS Classification Criteria.

Objective: To evaluate the applicability of the 2016 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR)/Paediatric Rheumatology International Trials Organisation (PRINTO) macrophage activation syndrome (MAS) classification criteria in patients with Still disease and systemic juvenile idiopathic arthritis (sJIA-SD) treated with interleukin-1 (IL-1)-targeted therapy and to assess the incidence of MAS in this context.

Methods: We analyzed retrospective and prospective data from Dutch patients with sJIA-SD (diagnosis 2008-2017, n = 54) and data from a nationwide prospective Dutch cohort and intervention study (diagnosis 2017-2022, n = 66). From these cohorts, MAS episodes developing in patients with sJIA-SD treated with IL-1-targeted therapy (anakinra or canakinumab) with at least two years of follow-up were selected.

Nicotinamide Inhibits CD4+ T-Cell Activation and Function.

Chronic inflammation and autoimmune diseases are driven, in part, by the activation of (auto)reactive CD4+ T-cells, highlighting their potential as therapeutic targets for these diseases. Nicotinamide (NAM) has demonstrated anti-inflammatory properties in various disease models and has already demonstrated safety in several large clinical trials in humans. The mechanisms behind these observations, and especially their direct effects on CD4+ T-cells, remain poorly understood.

Unmet needs and research gaps in Still's disease across ages: proceedings from a pediatric and adult joint expert panel.

Background: Still's disease (SD), including systemic juvenile idiopathic arthritis (sJIA) and adult-onset SD (AOSD), is an inflammatory condition typically characterized by daily fever, arthritis, and skin rash together with neutrophilic leukocytosis, thrombocytosis, and increased acute phase reactants. The reported differences between sJIA and AOSD appear to reflect variations along an inflammatory spectrum influenced by age, rather than differences in the underlying pathology.

Methods: In February 2023, an expert meeting, including pediatric and adult rheumatologists, was held in Rome, Italy, with the aim of defining more precise and timely strategies for disease management.

EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease.

Unlabelled: Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are considered the same disease, but a common approach for diagnosis and management is still missing.

Methods: In May 2022, EULAR and PReS endorsed a proposal for a joint task force (TF) to develop recommendations for the diagnosis and management of sJIA and AOSD. The TF agreed during a first meeting to address four topics: similarity between sJIA and AOSD, diagnostic biomarkers, therapeutic targets and strategies and complications including macrophage activation syndrome (MAS).

Validation of the EQ-5D-Y-5L parent-proxy version among children with juvenile idiopathic arthritis.

Objectives: Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children. It can cause joint pain and permanent physical damage, which affects mobility and daily activities. The EQ-5D-Y-3L self-report version has been validated in JIA, but the validity of EQ-5D-Y-5L remains unknown.

Get Spliced: Uniting Alternative Splicing and Arthritis.

Immune responses demand the rapid and precise regulation of gene protein expression. Splicing is a crucial step in this process; ~95% of protein-coding gene transcripts are spliced during mRNA maturation. Alternative splicing allows for distinct functional regulation, as it can affect transcript degradation and can lead to alternative functional protein isoforms.

Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis.

The cytokine storm syndrome (CSS) associated with systemic juvenile idiopathic arthritis (sJIA) has widely been referred to as macrophage activation syndrome (MAS). In this chapter, we use the term sJIA-associated CSS (sJIA-CSS) when referring to this syndrome and use the term MAS when referencing publications that specifically report on sJIA-associated MAS.

CBP/P300 Inhibition Impairs CD4+ T Cell Activation: Implications for Autoimmune Disorders.

T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood.

mA Reader YTHDC1 Impairs Respiratory Syncytial Virus Infection by Downregulating Membrane CX3CR1 Expression.

Respiratory syncytial virus (RSV) is the most prevalent cause of acute lower respiratory infection in young children. Currently, the first RSV vaccines are approved by the FDA. Recently, N6-methyladenosine (mA) RNA methylation has been implicated in the regulation of the viral life cycle and replication of many viruses, including RSV.

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic.

N6-methyladenosine promotes TNF mRNA degradation in CD4+ T lymphocytes.

N6-methyladenosine (m6A) is a RNA modification that can regulate post-transcriptional processes including RNA stability, translation, splicing, and nuclear export. In CD4+ lymphocytes, m6A modifications have been demonstrated to play a role in early differentiation processes. The role of m6A in CD4+ T cell activation and effector function remains incompletely understood.

The 4th NextGen Therapies for SJIA and MAS: part 1 the elephant in the room: diagnostic/classification criteria for systemic juvenile idiopathic arthritis and adult-onset still's disease.

Currently, the criteria used to classify patients with SJIA are different from those used for AOSD. However, it has been recognized that the existing terms are too narrow, subdividing the Still's population unnecessarily between pediatric-onset and adult-onset disease and excluding an appreciable group of children in whom overt arthritis is delayed or absent. Government regulators and insurers rely upon the guidance of subject experts to provide disease definitions, and when these definitions are flawed, to provide new and better ones.

The 4th NextGen therapies for SJIA and MAS: part 2 phenotypes of refractory SJIA and the landscape for clinical trials in refractory SJIA.

Although the introduction of the IL-1 and IL-6 inhibiting biologics in 2012 has revolutionized the treatment and markedly improved outcomes for many patients with SJIA, about 20% of these patients continue to have active disease, have markedly decreased quality of life and high disease activity as well as treatment-related morbidity and mortality. There is a clear need to define these disease states, and then use these definitions as the basis for further studies into the prevalence, clinical features, and pathophysiologic mechanisms. While such patients are most likely to benefit from novel therapies, they are very difficult to enroll in the ongoing clinical trials given the unique features of their disease and large numbers of background medications.

Quantifying hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNF-α inhibitors in juvenile idiopathic arthritis.

Objective: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNF-α inhibitors (TNFi) in JIA patients.

Methods: This was a retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalization) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal).

Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

Objectives: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm.

N-Methyladenosine Directly Regulates CD40L Expression in CD4 T Lymphocytes.

T cell activation is a highly regulated process, modulated via the expression of various immune regulatory proteins including cytokines, surface receptors and co-stimulatory proteins. N-methyladenosine (mA) is an RNA modification that can directly regulate RNA expression levels and it is associated with various biological processes. However, the function of mA in T cell activation remains incompletely understood.

Recombinant Interleukin-1 Receptor Antagonist Is an Effective First-Line Treatment Strategy in New-Onset Systemic Juvenile Idiopathic Arthritis, Irrespective of HLA-DRB1 Background and IL1RN Variants.

Objective: Human leukocyte antigen (HLA)-DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new-onset sJIA treated with anakinra as first-line therapy.

Withdrawing biologics in non-systemic JIA: what matters to pediatric rheumatologists?

Objective: Approximately one third of children with JIA receive biologic therapy, but evidence on biologic therapy withdrawal is lacking. This study aims to increase our understanding of whether and when pediatric rheumatologists postpone a decision to withdraw biologic therapy in children with clinically inactive non-systemic JIA.

Methods: A survey containing questions about background characteristics, treatment patterns, minimum treatment time with biologic therapy, and 16 different patient vignettes, was distributed among 83 pediatric rheumatologists in Canada and the Netherlands.

What matters most to pediatric rheumatologists in deciding whether to discontinue biologics in a child with juvenile idiopathic arthritis? A best-worst scaling survey.

Objectives: Care for JIA patients has been transformed in the biologics era; however, biologics carry important (although rare) risks and are costly. Flares after biological withdrawal are seen frequently, yet there is little clinical guidance to identify which patients in clinical remission can safely have their biologic discontinued (by stopping or tapering). We examined what characteristics of the child or their context are important to pediatric rheumatologists when making the decision to discuss withdrawal of biologics.

Meningococcal ACWY conjugate vaccine immunogenicity and safety in adolescents with juvenile idiopathic arthritis and inflammatory bowel disease: A prospective observational cohort study.

Background: Immunogenicity to meningococcal serogroup ACWY (MenACWY) conjugate vaccine has not been studied in immunocompromised minors with juvenile idiopathic arthritis (JIA) or inflammatory bowel disease (IBD). We determined immunogenicity of a MenACWY-TT vaccine in JIA and IBD patients at adolescent age and compared results to data from aged-matched healthy controls (HCs).

Methods: We performed a prospective observational cohort study in JIA and IBD patients (14-18 years old), who received a MenACWY vaccination during a nationwide catch-up campaign (2018-2019) in the Netherlands.

Conventional dendritic cells type 1 are strongly enriched, quiescent and relatively tolerogenic in local inflammatory arthritis.

Introduction: Dendritic cells (DC) are crucial for initiating and shaping immune responses. So far, little is known about the functional specialization of human DC subsets in (local) inflammatory conditions. We profiled conventional (c)DC1, cDC2 and monocytes based on phenotype, transcriptome and function from a local inflammatory site, namely synovial fluid (SF) from patients suffering from a chronic inflammatory condition, Juvenile Idiopathic Arthritis (JIA) as well as patients with rheumatoid arthritis (RA).

Epigenetic changes in inflammatory arthritis monocytes contribute to disease and can be targeted by JAK inhibition.

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.