Research agenda setting with children with juvenile idiopathic arthritis: Lessons learned.

AIM: The aim of this qualitative study is to understand the research priorities of Dutch children with juvenile idiopathic arthritis (JIA) as well as researching how children can be involved. BACKGROUND: Several health research agendas have successfully been developed with adults but rarely with children. Children are still seldom recognized as possessing credible knowledge about their own body and life. This research project with focus group discussions and interviews with children with juvenile idiopathic arthritis (JIA) was an innovative addition to a nationwide prioritization of research questions of patients with JIA, their carers and health care professionals, based on the James Lind Alliance (JLA) methodology. RESULTS: Children with JIA appreciated being invited to give their opinion on JIA research prioritization as knowledgeable actors. They have clear views on what topics need most attention. They want more insight on how to medically and socially treat JIA so that they can better fulfil their aspirations at school, later in work and with their relationships. CONCLUSION: We have identified the Top 5 research priorities for children with JIA. Most priorities are unique and differ from the priorities of the adolescents and young adults, parents and healthcare professionals in the main JLA priority setting exercise. Ultimately, two of the children's priorities were included in the final JLA Top 10.

Prediction of relapse after discontinuation of infliximab therapy in severe sarcoidosis.

Infliximab is effective as a third-line therapeutic for severe sarcoidosis; however, long-term efficacy is unknown. The aim of this study was to assess the relapse rate after discontinuation of infliximab in sarcoidosis patients and predict relapse by analysis of the activity marker soluble interleukin (IL)-2 receptor (sIL-2R) and maximum standardised uptake value (SUVmax) of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). In this retrospective cohort study, the proportion of relapse was analysed using the Kaplan-Meier method and predicting factors were studied using Cox regression. 47 sarcoidosis patients who started infliximab therapy were included in the risk analysis. Kaplan-Meier analysis revealed a median time to relapse of 11.1 months and showed that 25% of the cohort relapsed within 4 months. Both mediastinal SUVmax ≥ 6.0 on FDG PET (hazard ratio 3.77, p<0.001) and serum sIL-2R ≥ 4000 pg · mL(-1) (hazard ratio 2.24, p=0.033) at start of therapy predicted relapse. In multivariate analysis, a mediastinal SUVmax ≥ 6.0 at initiation of therapy was an independent predictor of relapse (hazard ratio 4.33, p<0.001). The majority of patients that discontinued infliximab therapy relapsed. High serum sIL-2R and high SUVmax on FDG PET at initiation of therapy were significant predictors of relapse. These results suggest close monitoring of patients in this category when they discontinue infliximab treatment.

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. METHODS: HLA and IL1RN risk alleles were identified via whole-genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. RESULTS: Seventeen of 65 patients (26%) carried HLA-DRB1*15:01, comparable with the general population, and there was enrichment for HLA-DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA-DRB1 or IL1RN variants, but significantly lower in carriers of an HLA-DRB1*11:01 allele. One patient, an HLA-DRB1*15:01 carrier, developed sJIA-LD. Of the three patients with severe drug reactions to biologics, one carried HLA-DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA-DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). CONCLUSION: We observed high rates of CID using anakinra as first-line treatment irrespective of HLA-DRB1 or IL1RN variants. Only one of the 17 HLA-DRB1*15:01 carriers developed sJIA-LD, and of the three patients with drug reactions to biologics, only one carried HLA-DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA-LD, remains important, our data support the early start of biologic therapy in patients with new-onset sJIA irrespective of HLA-DRB1 background or IL1RN variants.

Dutch patients, caregivers and healthcare professionals generate first nationwide research agenda for juvenile idiopathic arthritis.

BACKGROUND: Involving the end-users of scientific research (patients, carers and clinicians) in setting research priorities is important to formulate research questions that truly make a difference and are in tune with the needs of patients. We therefore aimed to generate a national research agenda for Juvenile Idiopathic Arthritis (JIA) together with patients, their caregivers and healthcare professionals through conducting a nationwide survey among these stakeholders. METHODS: The James Lind Alliance method was used, tailored with additional focus groups held to involve younger patients. First, research questions were gathered through an online and hardcopy survey. The received questions that were in scope were summarised and a literature search was performed to verify that questions were unanswered. Questions were ranked in the interim survey, and the final top 10 was chosen during a prioritisation workshop. RESULTS: Two hundred and seventy-eight respondents submitted 604 questions, of which 519 were in scope. Of these 604 questions, 81 were generated in the focus groups with younger children. The questions were summarised into 53 summary questions. An evidence checking process verified that all questions were unanswered. A total of 303 respondents prioritised the questions in the interim survey. Focus groups with children generated a top 5 of their most important questions. Combining this top 5 with the top 10s of patients, carers, and clinicians led to a top 21. Out of these, the top 10 research priorities were chosen during a final workshop. Research into pain and fatigue, personalised treatment strategies and aetiology were ranked high in the Top 10. CONCLUSIONS: Through this study, the top 10 research priorities for JIA of patients, their caregivers and clinicians were identified to inform researchers and research funders of the research topics that matter most to them. The top priority involves the treatment and mechanisms behind persisting pain and fatigue when the disease is in remission.

Recommendations from a James Lind Alliance priority setting partnership - a qualitative interview study.

BACKGROUND: The James Lind Alliance (JLA) offers a method for research priority setting with patients, clinicians and carers. The method is increasingly used but publications primarily discuss the outcome of such projects, rather than reflecting on the JLA method itself. Scrutiny of the method is crucial in order to understand and correctly interpret its outcomes. METHODS: We conducted a qualitative interview study with people involved in a JLA project into Juvenile Idiopathic Arthritis (JIA) (n = 30) to better understand the mechanisms, procedures and decisional processes during such a project and to formulate recommendations for those who consider starting a JLA project in the future. RESULTS: Four main themes were identified: 1) motivations, goals and expectations 2) inclusivity, roles and representation 3) procedures and decision-making 4) outcomes and future steps. CONCLUSION: While the top 10 of 'evidence uncertainties' seems to take the centre stage in JLA projects, the ways in which these priorities are determined may be influenced by 'process uncertainties'. We have formulated ten specific recommendations for future JLA projects. Reflection on and reporting of these process uncertainties would contribute to the improvement of JLA projects and increase the validity of the outcome of such projects.

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

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-1ß 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.

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

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.

The human microbiome and juvenile idiopathic arthritis.

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.

Role of mast cells in mucosal diseases: current concepts and strategies for treatment.

Mast cells are well known for their role in type I hypersensitivity. However, their role in the immune system as well as their pathophysiological role in other diseases is underacknowledged. The role of mast cells in inflammatory bowel disease, allergic contact dermatitis and asthma is illustrated in this review. The contribution of mast cell activation in these diseases is controversial and two alternative means are proposed: activation via stress response pathways and immunoglobulin-free light chains. Activation of the mast cells leads to release of preformed mediators and to generation of other potent biological substances that have both physiological and pathophysiological effects. The role of these mediators in the aforementioned diseases is also outlined in this review. When the roles of mast cells are better understood, drugs specifically targeting mast cells may be developed to effectively treat a wide range of diseases.