No evidence that genetic predictors of susceptibility predict changes in core outcomes in JIA

Objectives. The clinical progression of JIA is unpredictable. Knowing who will develop severe disease could facilitate rapid intensification of therapies. We use genetic variants conferring susceptibility to JIA to predict disease outcome measures. Methods. A total of 713 JIA patients with genotype data and core outcome variables (COVs) at diagnosis (baseline) and 1 year follow-up were identified from the Childhood Arthritis Prospective Study (CAPS). A weighted genetic risk score (GRS) was generated, including all single nucleotide polymorphisms (SNPs) previously associated with JIA susceptibility (P-value<5 10 08). We used multivariable linear regression to test the GRS for association with COVS (limited joint count, active joint count, physician global assessment, parent/patient general evaluation, childhood HAQ and ESR) at baseline and change in COVS from baseline to 1 year, adjusting for baseline COV and International League of Associations of Rheumatology (ILAR) category. The GRS was split into quintiles to identify high (quintile 5) and low (quintile 1) risk groups. Results. Patients in the high-risk group for the GRS had a younger age at presentation (median low risk 7.79, median high risk 3.51). No association was observed between the GRS and any outcome measures at 1 year follow-up or baseline. Conclusion. For the first time we have used all known JIA genetic susceptibility loci (P¼<5 10 08) in a GRS to predict changes in disease outcome measured over time. Genetic susceptibility variants are poor predictors of changes in core outcome measures, it is likely that genetic factors predicting disease outcome are independent to those predicting susceptibility. The next step will be to conduct a genome-wide association analysis of JIA outcome.Versus Arthritis 20542 22084 20621Centre for Epidemiology Versus Arthritis (UK) 21755National Institute for Health Research (NIHR)Manchester Academic Health Sciences Centre (MAHSC)CLUSTER consortiumUK Research & Innovation (UKRI)Medical Research Council UK (MRC) MR/R013926/1Great Ormond Street Hospital Children's Charity VS0518Olivia's VisionNIHR GOSH BRC'UK's Experimental Arthritis Treatment Centre for Children by Versus Arthritis 20621NIHR GOSH Biomedical Research CentreBritish Society for Rheumatology (BSR

Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA)

The cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations

Association of the CCR5 gene with juvenile idiopathic arthritis

The CC chemokine receptor 5 (CCR5) has been shown to be important in the recruitment of T-helper cells to the synovium, where they accumulate, drive the inflammatory process and the consequent synovitis and joint destruction. A 32 base-pair insertion/deletion variant (CCR5Δ32) within the gene leads to a frame shift and a nonfunctional receptor. CCR5Δ32 has been investigated for its association with juvenile idiopathic arthritis (JIA), with conflicting results. The aim of this study was to investigate whether CCR5Δ32 is associated with JIA in an UK population. CCR5Δ32 was genotyped in JIA cases (n=1054) and healthy controls (n=3129) and genotype and allele frequencies were compared. A meta-analysis of our study combined with previously published studies was performed. CCR5Δ32 was significantly associated with protection from developing JIA, in this UK data set (P(trend)=0.006, odds ratio (OR) 0.79 95% confidence interval (95% CI): 0.66-0.94). The meta-analysis of all published case-control association studies confirmed the protective association with JIA (P=0.001 OR 0.82 95% CI: 0.73-0.93). CCR5Δ32 is a functional variant determining the number of receptors on the surface of T cells, and it is hypothesized that the level of CCR5 expression could influence the migration of proinflammatory T cells into the synovium and thus susceptibility to JIA

Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap

Peer reviewedPublisher PD

Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is an umbrella term for all chronic childhood arthropathies and can be divided into seven subtypes. It includes the enthesitis related arthritis (ERA) subtype which displays symptoms similar to ankylosing spondylitis (AS) and juvenile-onset psoriatic arthritis which has similarities to psoriatic arthritis (PsA) and psoriasis (Ps). We, therefore, hypothesized that two well-established susceptibility loci for AS and Ps, ERAP1 and IL23R, could also confer susceptibility to these JIA subtypes. METHODS: Single nucleotide polymorphisms (SNPs) in ERAP1 (rs30187) and IL23R (rs11209026) were genotyped in JIA cases (n = 1,054) and healthy controls (n = 5,200). Genotype frequencies were compared between all JIA cases and controls using the Cochrane-Armitage trend test implemented in PLINK. Stratified analysis by ILAR subtype was performed. RESULTS: The ERA subtype showed strong association with ERAP1 SNP (P trend = 0.005). The IL23R SNP showed significant association in the PsA subtype (P trend = 0.04). The SNPs were not associated with JIA overall or with any other subtype. CONCLUSIONS: We present evidence for subtype specific association of the ERAP1 gene with ERA JIA and the IL23R gene with juvenile-onset PsA. The findings will require validation in independent JIA datasets. These results suggest distinct pathogenic pathways in these subtypes

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

Recent genetic studies have led to identification of numerous loci that are associated with susceptibility to autoimmune diseases. The strategy of using information from these studies has facilitated the identification of novel juvenile idiopathic arthritis (JIA) susceptibility loci, specifically, PTPN22 and IL2RA. Several novel autoimmune susceptibility loci have recently been identified, and we hypothesise that single-nucleotide polymorphisms (SNPs) within these genes may also be JIA susceptibility loci. Five SNPs within the genes AFF3, IL2/IL21, IL7R, CTLA4 and CD226, previously associated with multiple autoimmune diseases were genotyped, in a large data set of Caucasian JIA patients and controls, and tested for association with JIA. We identified two susceptibility loci for JIA, AFF3 and the IL2/IL21 region and additional weak evidence supporting an association with the CTLA4 and IL7R genes, which warrant further investigation. All results require validation in independent JIA data sets. Further characterisation of the specific causal variants will be required before functional studies can be performed

Validating a pain perception questionnaire for young people with juvenile arthritis

Background: The ways in which people perceive their illness are known to affect long-term outcomes. The Common Sense-Self-Regulatory Model (CS-SRM) is used as a theoretical framework to investigate the influence of illness beliefs on outcomes and the Revised Illness Perception Questionnaire (IPQ-R) is used to assess key illness beliefs. However, these approaches have rarely been used with adolescents nor is there a validated adolescent version of the IPQ-R. The aim of this work is to develop an illness perception questionnaire for adolescents with JIA. Methods: The first phase was a two-stage qualitative analysis of transcripts from cognitive interviews with 20 adolescents. It became clear that participants focused on their main symptom of JIA, in this case pain, rather than JIA. Modifications to IPQ-R items were undertaken to devise the first version of the Pain Perception Questionnaire for Young People (PPQ-YP). It was then sent to 18 adolescents aged between 11 and 16 years to assess linguistic and face validity. Participants were asked to think of a recent pain to answer the questionnaire and provide feedback on the language and length. After further modifications, the PPQ-YP was sent to 65 patients with JIA to test further psychometric properties. Results: The thematic analysis showed that episodic and unpredictable nature of JIA pain experiences meant that the existing adult version of the IPQ-R did not adequately capture adolescents’ pain beliefs. Furthermore, the adolescents reported that their behaviour was determined by their pain experiences. The content analysis of feedback about of the IPQ-R showed which items elicited the most problems. For example, negatively worded items led ‘incongruent endorsement’ meaning that responses to these items reflected the opposite response to the one intended. These results in addition to the thematic analysis determined the modifications of the IPQ-R and the development of new items of the PPQ-YP. The participants who reviewed the PPQ-YP completed a detailed feedback questionnaire and this led to further modifications. 65 adolescents with juvenile arthritis completed version 2, Cronbach’s alpha for the domains ranged from 0.60 for personal control to 0.93 for emotional representation. Further validation and re-test reliability testing of this version of the PPQ-YP is currently underway. Conclusion: Currently, there are no validated adolescent questionnaires that capture the full range of pain beliefs related to JIA. The PPQ-YP is a theory-driven questionnaire consisting of nine domains of pain beliefs. By using a framework that clearly defines the relationship between beliefs outcomes it is hoped that data generated by the PPQ-YP will provide stronger predictors of an adolescent’s behaviour by facilitating better assessment of adolescent beliefs. This can lead to the development of new interventions for adolescents with JIA

OP0157-HPR “This feeling!” : can a new Ipad app help children with juvenile idiopathic arthritis communicate their pain experiences? Feasibility, usability and acceptability

Background Pain is the most common symptom of Juvenile Idiopathic Arthritis (JIA), and it is known to cause significant distress for young people. Despite advances in treatment, pain is often still poorly managed. Multidimensional approaches are needed to help children with JIA communicate better about their pain experiences with healthcare professionals and parents. A new interactive iPad application called “This Feeling” has been developed in collaboration with children and healthcare professionals to aid communication about pain in children with JIA. “This Feeling” enables young people to describe the pain type, intensity, location, spread and emotional impact at a given time, by using an interactive manikin, adjustable pain icons, facial expressions, drawing tools and free text description. Objectives The aim of this research was to explore the acceptability, usability and feasibility of “This Feeling” to communicate pain experiences in children with JIA by comparing the tool with self-report measures commonly used in clinic: the Visual Analogue Scale (VAS) and The Faces Pain Scale, Revised (FPS-R). Methods Young people aged between 5 and 16 and consenting caregivers were recruited from a city centre hospital in England, which was part of the Childhood Arthritis Prospective Study (CAPS), a large scale prospective inception cohort. A cross-sectional design using mixed methods compared self-report measures (the VAS and FPS-R) with “This Feeling”. The measures were administered in random order to young people attending an outpatients' clinic. Semi-structured interviews were used to elicit views on completing “This Feeling” compared with standardised measures. Results The sample consisted of 43 young people and their caregivers. All participants were able to use “This Feeling” to describe their pain experiences (average completion time 8 minutes). The majority (95%) preferred using “This Feeling” over the VAS and FPS-R, and found it easier and more interesting to communicate their pain experiences. Participants suggested modifications including a zoom function as well as an icon to indicate “No Pain”. Usability feedback indicated that the shading function interfered with pain icons which young people had already placed on the manikin. Parents praised “This Feeling” for capturing the multidimensional nature of pain in an easy and “child friendly” nature, over the conventional pain measures. Conclusions “This Feeling” appears to be a feasible, usable and acceptable system for communicating the multidimensional nature of pain in children with JIA. Future modifications will be addressed. Plans are being made to validate the different components of “This Feeling”, specifically, the facial expressions, the body map and pain severity and intensity scales to develop this further as a pain assessment tool