Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.

OBJECTIVES: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients. METHODS: Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. RESULTS: Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. CONCLUSION: Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.

Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study.

BACKGROUND: In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary. AIM: To explore 'real world' treatment utilising longitudinal UK JSLE Cohort Study data. METHODS: Data collected between 07/2009-05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice. RESULT: 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65-2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator. CONCLUSIONS: Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly.

Attainment of low disease activity and remission targets reduces the risk of severe flare and new damage in childhood lupus.

OBJECTIVES: To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood-onset SLE (cSLE). METHODS: Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen gap recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage. RESULTS: LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (P < 0.001). As cumulative time in each target increased, hazard of severe flare progressively reduced. LLDAS attainment reduced the hazard of severe flare more than LA or Toronto-LDA (P < 0.001). Attainment of LLDAS and all remission definitions led to a statistically comparable reduction in the hazards of severe flare (P > 0.05). Attainment of all targets reduced the hazards of new damage (P < 0.05). CONCLUSIONS: This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical remission.

Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus: Data from the UK Juvenile-onset systemic lupus erythematosus cohort study.

INTRODUCTION: Juvenile-onset systemic lupus erythematosus (JSLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Neuropsychiatric (NP) involvement is a severe complication, encompassing a heterogeneous range of neurological and psychiatric manifestations. METHODS: Demographic, clinical, and laboratory features of NP-SLE were assessed in participants of the UK JSLE Cohort Study, and compared to patients in the same cohort without NP manifestations. RESULTS: A total of 428 JSLE patients were included in this study, 25% of which exhibited NP features, half of them at first visit. Most common neurological symptoms among NP-JSLE patients included headaches (78.5%), mood disorders (48.6%), cognitive impairment (42%), anxiety (23.3%), seizures (19.6%), movement disorders (17.7%), and cerebrovascular disease (14.9%). Peripheral nervous system involvement was recorded in 7% of NP-SLE patients. NP-JSLE patients more frequently exhibited thrombocytopenia (<100 × 109/L) (p = 0.04), higher C-reactive protein levels (p = 0.01), higher global pBILAG score at first visit (p < 0.001), and higher SLICC damage index score at first (p = 0.02) and last (p < 0.001) visit when compared to JSLE patients without NP involvement. CONCLUSIONS: A significant proportion of JSLE patients experience NP involvement (25%). Juvenile-onset NP-SLE most commonly affects the CNS and is associated with increased overall disease activity and damage.

Limited sensitivity and specificity of the ACR/EULAR-2019 classification criteria for SLE in JSLE?-observations from the UK JSLE Cohort Study.

OBJECTIVES: This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE. METHODS: Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria. RESULTS: At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%). CONCLUSION: In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes.

Clinical and laboratory phenotypes in juvenile-onset Systemic Lupus Erythematosus across ethnicities in the UK.

Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease. Patients diagnosed with juvenile-onset SLE (jSLE), when compared to individuals with adult-onset SLE, develop more severe organ involvement, increased disease activity and greater tissue and organ damage. In adult-onset SLE, clinical characteristics, pathomechanisms, disease progression and outcomes do not only vary between individuals and age groups, but also ethnicities. However, in children and young people, the influence of ethnicity on disease onset, phenotype and outcome has not been investigated in detail. In this study, we investigated clinical and laboratory characteristics in pediatric SLE patients from different ethnic backgrounds (White Caucasian, Asian, Black African/Caribbean) accessing data from a national cohort of jSLE patients (the UK JSLE Cohort Study). Among jSLE patients in the UK, ethnicity affects both the disease's clinical course and outcomes. At diagnosis, Black African/Caribbean jSLE patients show more "classical" laboratory and clinical features when compared to White Caucasian or Asian patients. Black African/Caribbean jSLE patients exhibit more renal involvement and more frequently receive cyclophosphamide and rituximab. Studies targeting ethnicity-specific contributors to disease expression and phenotypes are necessary to improve our pathophysiological understanding, diagnosis and treatment of jSLE.

The prevention and treatment of glucocorticoid-induced osteopaenia in juvenile rheumatic disease: A randomised double-blind controlled trial.

BACKGROUND: Children and young people (CYP) with chronic rheumatic conditions; Juvenile Idiopathic Arthritis, Juvenile Systemic Lupus Erythematosus, Juvenile Dermatomyositis and Juvenile Vasculitis, treated with steroids, have low bone density, increased fracture risk and are likely to have suboptimal peak bone mass. There is currently no evidence base for the management of steroid-induced bone loss in children with rheumatic diseases. METHODS: We undertook a multi-centre double dummy double-blind randomised placebo controlled trial to investigate whether the bisphosphonate risedronate was superior to alfacalcidol or calcium and vitamin D supplementation in the prevention and treatment of steroid-induced osteopaenia in these children. Patients were stratified and randomised in a 1:1 ratio, into: placebo; alfacalcidol; risedronate. The primary outcome was the change in lumbar spine bone mineral density z score (LSaBMDz) measured by dual energy x-ray absorptiometry at one year. Secondary outcome was fracture rate. RESULTS: Two hundred and seventeen patients were recruited to the study. Seventy seven placebo, 71 alfacalcidol, and 69 risedronate. Highly statistically significant differences were observed in the change in LSaBMDz between the placebo and risedronate groups; 0.274, 95% CI (0.061, 0.487) (p < 0.001) and between the risedronate and the alfacalcidol groups; 0.326 95% CI (0.109, 0.543) (p < 0.001). The difference observed between the alfacalcidol and placebo group was not statistically significant.Highly statistically significant differences were seen in the change in Total Body Less Head aBMD-Z Score between the placebo and risedronate groups (p < 0.01) but not between the alfacalcidol and risedronate groups. No significant differences in fracture frequency, adverse or serious adverse reactions were observed between the groups. CONCLUSIONS: Children and adolescents receiving steroids for rheumatic diseases benefit from prophylactic treatment with bisphosphonates to increase LSaBMD. Alfacalcidol is ineffective.

Acid Ceramidase Deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy.

Acid Ceramidase Deficiency (Farber disease, FD) is an ultra-rare Lysosomal Storage Disorder that is poorly understood and often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Hallmarks of FD are accumulation of ceramides, widespread macrophage infiltration, splenomegaly, and lymphocytosis. The cytokines involved in this abnormal hematopoietic state are unknown. There are dozens of ceramide species and derivatives, but the specific ones that accumulate in FD have not been investigated. We used a multiplex assay to analyze cytokines and mass spectrometry to analyze ceramides in plasma from patients and mice with FD, controls, Farber patients treated by hematopoietic stem cell transplantation (HSCT), JIA patients, and patients with Gaucher disease. KC, MIP-1α, and MCP-1 were sequentially upregulated in plasma from FD mice. MCP-1, IL-10, IL-6, IL-12, and VEGF levels were elevated in plasma from Farber patients but not in control or JIA patients. C16-Ceramide (C16-Cer) and dhC16-Cer were upregulated in plasma from FD mice. a-OH-C18-Cer, dhC12-Cer, dhC24:1-Cer, and C22:1-Cer-1P accumulated in plasma from patients with FD. Most cytokines and only a-OH-C18-Cer returned to baseline levels in HSCT-treated Farber patients. Sphingosines were not altered. Chitotriosidase activity was also relatively low. A unique cytokine and ceramide profile was seen in the plasma of Farber patients that was not observed in plasma from HSCT-treated Farber patients, JIA patients, or Gaucher patients. The cytokine profile can potentially be used to prevent misdiagnosis of Farber as JIA and to monitor the response to treatment. Further understanding of why these signaling molecules and lipids are elevated can lead to better understanding of the etiology and pathophysiology of FD and inform development of future treatments.

Faecal Calprotectin in Treated and Untreated Children With Coeliac Disease and Juvenile Idiopathic Arthritis.

The present study aimed to provide evidence on whether children at risk of gastrointestinal inflammation have increased measurements of faecal calprotectin (FC). FC was measured in 232 children; 55 children (n = 11 treatment naïve) with juvenile idiopathic arthritis (JIA), 63 with coeliac disease (CD); 17 with new diagnosis before and after treatment on gluten-free diet and 114 controls. None of the treatment-naive children with JIA had raised FC. Four JIA patients on treatment had a raised FC but in all cases a repeat test was normal. In newly diagnosed patients with CD, the median (interquartile range) FC was higher 36.4 (26-61) than that in controls 25.0 (23-41) mg/kg (P = 0.045) but this significantly decreased 25 (25-25) mg/kg (P = 0.012) after 6 months on gluten-free diet. Random measurements of FC are not raised in children with JIA or CD. A significant elevation of FC in these groups is not explained by their diagnosis and therefore needs further investigation.

Influence of past breast feeding on pattern and severity of presentation of juvenile idiopathic arthritis.

This analysis aimed to study the influence of breast feeding on the pattern and severity of juvenile idiopathic arthritis (JIA) at presentation. The association between ever versus never breast feeding and disease severity at onset was compared in 923 children with JIA recruited to the UK Childhood Arthritis Prospective Study at first presentation to rheumatology. Fifty six per cent of children were ever breast fed (median 3.7 months). Breastfed children reported a lower median age at onset, a lower Childhood Health Assessment Questionnaire (CHAQ), a measure of disease severity, lower parent general evaluation scores and lower pain at presentation. There was a trend towards a higher proportion of breastfed children with rheumatoid factor-negative polyarthritis, but lesser enthesitis-related and psoriatic arthritis. There was a statistically significant inverse association between breast feeding and high CHAQ, even after adjusting for differences in socioeconomic status (adjusted OR 0.61 (95% CI 0.39 to 0.95)). Further work to understand the reasons behind these associations is required.

Mucocutaneous manifestations in a UK national cohort of juvenile-onset systemic lupus erythematosus patients.

OBJECTIVE: To determine whether mucocutaneous manifestations are associated with major organ involvement in a UK national cohort of juvenile-onset SLE (JSLE) patients. METHODS: JSLE patients (n = 241) from 15 different centres whose diagnosis fulfilled four or more of the ACR criteria were divided into two groups: those with at least one ACR mucocutaneous criterion (ACR skin feature positive) and those without (ACR skin feature negative) at diagnosis. The relative frequency of skin involvement was described by the paediatric adaptation of the 2004 British Isles Lupus Assessment Group (pBILAG-2004) index. RESULTS: One hundred and seventy-nine patients (74%) had ACR-defined skin involvement with no significant demographic differences compared with those without. ACR skin feature negative patients showed greater haematological (84% vs 67%), renal (43% vs 26%) (P < 0.05) and neurological (16% vs 4%) involvement (P = 0.001). Forty-two per cent of ACR skin feature negative patients had skin involvement using pBILAG-2004, which included maculopapular rash (17%), non-scaring alopecia (15%), cutaneous vasculitis (12%) and RP (12%). ACR skin feature negative patients with moderate to severe skin involvement by pBILAG-2004 showed greater renal and haematological involvement at diagnosis and over the follow-up period (P < 0.05). Higher immunosuppressive drug use in the skin feature negative group was demonstrated. CONCLUSION: Patients who fulfil the ACR criteria but without any of the mucocutaneous criteria at diagnosis have an increased risk of major organ involvement. The pBILAG-2004 index has shown that other skin lesions may go undetected using the ACR criteria alone, and these lesions show a strong correlation with disease severity and major organ involvement.

An exploration of parents' preferences for foot care in juvenile idiopathic arthritis: a possible role for the discrete choice experiment.

BACKGROUND: An increased awareness of patients' and parents' care preferences regarding foot care is desirable from a clinical perspective as such information may be utilised to optimise care delivery. The aim of this study was to examine parents' preferences for, and valuations of foot care and foot-related outcomes in juvenile idiopathic arthritis (JIA). METHODS: A discrete choice experiment (DCE) incorporating willingness-to-pay (WTP) questions was conducted by surveying 42 parents of children with JIA who were enrolled in a randomised-controlled trial of multidisciplinary foot care at a single UK paediatric rheumatology outpatients department. Attributes explored were: levels of pain; mobility; ability to perform activities of daily living (ADL); waiting time; referral route; and footwear. The DCE was administered at trial baseline. DCE data were analysed using a multinomial-logit-regression model to estimate preferences and relative importance of attributes of foot care. A stated-preference WTP question was presented to estimate parents' monetary valuation of health and service improvements. RESULTS: Every attribute in the DCE was statistically significant (p < 0.01) except that of cost (p = 0.118), suggesting that all attributes, except cost, have an impact on parents' preferences for foot care for their child. The magnitudes of the coefficients indicate that the strength of preference for each attribute was (in descending order): improved ability to perform ADL, reductions in foot pain, improved mobility, improved ability to wear desired footwear, multidisciplinary foot care route, and reduced waiting time. Parents' estimated mean annual WTP for a multidisciplinary foot care service was £1,119.05. CONCLUSIONS: In terms of foot care service provision for children with JIA, parents appear to prefer improvements in health outcomes over non-health outcomes and service process attributes. Cost was relatively less important than other attributes suggesting that it does not appear to impact on parents' preferences.

The effectiveness of a multidisciplinary foot care program for children and adolescents with juvenile idiopathic arthritis: an exploratory trial.

OBJECTIVES: To evaluate the effectiveness of multidisciplinary foot-care, and to evaluate the methodological considerations of a trial of multidisciplinary care in juvenile idiopathic arthritis. DESIGN: Exploratory randomised controlled trial. SUBJECTS/PATIENTS: Children/adolescents with juvenile idio-pathic arthritis and inflammatory joint disease affecting the foot/ankle. METHODS: Standard medical care was compared with a 12 month program of multidisciplinary foot-care informed by musculoskeletal ultrasound. This program was centred on strict disease control through rigorous examination and interventions delivered by a team comprised of a paediatric rheumatologist, podiatrist, physiotherapist and musculoskeletal ultrasonographer. Patients were assessed on foot impairment and disability scores using the Juvenile Arthritis Foot Disability Index. RESULTS: Forty-four participants, aged 3-17 years were randomly assigned to receive the experimental (n = 21) or usual care (n = 23) interventions. There was an overall improvement in levels of foot related impairments in both groups over 12 months. Between-group differences in change scores for the Juvenile Arthritis Foot Disability Index were not statistically significant at 6 or 12 month follow-ups. CONCLUSION: The integrated multidisciplinary foot care interventions described in this trial were safe, but did not improve foot impairment levels relative to usual care. This trial identified several methodological challenges including recruitment/retention, difficulties with outcome tools and potential confounders.

Validity of a three-variable Juvenile Arthritis Disease Activity Score in children with new-onset juvenile idiopathic arthritis.

OBJECTIVES: To investigate the validity and feasibility of the Juvenile Arthritis Disease Activity Score (JADAS) in the routine clinical setting for all juvenile idiopathic arthritis (JIA) disease categories and explore whether exclusion of the erythrocyte sedimentation rate (ESR) from JADAS (the 'JADAS3') influences correlation with single markers of disease activity. METHODS: JADAS-71, JADAS-27 and JADAS-10 were determined at baseline for an inception cohort of children with JIA in the Childhood Arthritis Prospective Study. JADAS3-71, JADAS3-27 and JADAS3-10 were determined using an identical formula but with exclusion of ESR. Correlation of JADAS with JADAS3 and single measures of disease activity/severity were determined by category. RESULTS: Of 956 eligible children, sufficient data were available to calculate JADAS-71, JADAS-27 and JADAS-10 at baseline in 352 (37%) and JADAS3 in 551 (58%). The median (IQR) JADAS-71, JADAS-27 and JADAS-10 for all 352 children was 11 (5.9-18), 10.4 (5.7-17) and 11 (5.9-17.3), respectively. Median JADAS and JADAS3 varied significantly with the category (Kruskal-Wallis p=0.0001), with the highest values in children with polyarticular disease patterns. Correlation of JADAS and JADAS3 across all categories was excellent. Correlation of JADAS71 with single markers of disease activity/severity was good to moderate, with some variation across the categories. With the exception of ESR, correlation of JADAS3-71 was similar to correlation of JADAS-71 with the same indices. CONCLUSIONS: This study is the first to apply JADAS to all categories of JIA in a routine clinical setting in the UK, adding further information about the feasibility and construct validity of JADAS. For the majority of categories, clinical applicability would be improved by exclusion of the ESR.

Foot function is well preserved in children and adolescents with juvenile idiopathic arthritis who are optimally managed.

PURPOSE: The objective of this study was to compare disease activity, impairments, disability, foot function and gait characteristics between a well described cohort of juvenile idiopathic arthritis (JIA) patients and normal healthy controls using a 7-segment foot model and three-dimensional gait analysis. METHODS: Fourteen patients with JIA (mean (standard deviation) age of 12.4 years (3.2)) and a history of foot disease and 10 healthy children (mean (standard deviation) age of 12.5 years (3.4)) underwent three-dimensional gait analysis and plantar pressure analysis to measure biomechanical foot function. Localised disease impact and foot-specific disease activity were determined using the juvenile arthritis foot disability index, rear- and forefoot deformity scores, and clinical and musculoskeletal ultrasound examinations respectively. Mean differences between groups with associated 95% confidence intervals were calculated using the t distribution. RESULTS: Mild-to-moderate foot impairments and disability but low levels of disease activity were detected in the JIA group. In comparison with healthy subjects, minor trends towards increased midfoot dorsiflexion and reduced lateral forefoot abduction within a 3-5° range were observed in patients with JIA. The magnitude and timing of remaining kinematic, kinetic and plantar pressure distribution variables during the stance phase were similar for both groups. CONCLUSION: In children and adolescents with JIA, foot function as determined by a multi-segment foot model did not differ from that of normal age- and gender-matched subjects despite moderate foot impairments and disability scores. These findings may indicate that tight control of active foot disease may prevent joint destruction and associated structural and functional impairments.

Juvenile-onset inflammatory arthritis: a study of adolescents' beliefs about underlying cause.

OBJECTIVE: Patients' beliefs regarding the cause of illness may influence treatment adherence and long-term outcome. Little is known of adolescents' beliefs regarding the cause of JIA. This study aims to identify adolescents' beliefs about the underlying cause of their arthritis at first presentation to the paediatric rheumatology department. METHODS: One hundred and twenty-two adolescents aged ≥11 years participating in the larger prospective Childhood Arthritis Prospective Study, an inception cohort of childhood-onset inflammatory arthritis, were asked to complete a questionnaire regarding underlying beliefs about their arthritis. The top-listed causes were identified, and associations between beliefs and characteristics of the adolescents and their arthritis were compared across the different causal beliefs. RESULTS: The most common causal beliefs were genetics (27.1%), the immune system (21.3%), accident or injury (15.6%) and infection (13.1%). Association between causal beliefs and gender, disease duration, International League Against Rheumatism subtype and source of referral was observed, although small numbers prevented robust statistical comparisons. CONCLUSION: This first report on adolescents' beliefs about the cause of their juvenile arthritis found the most common causal beliefs to be related to genes or the immune system. Brief assessments of adolescents' beliefs at presentation will enable providers to modify or adapt potentially unhelpful beliefs and provide age-appropriate information regarding arthritis.

Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort.

OBJECTIVE: The UK Juvenile-Onset Systemic Lupus Erythematosus (JSLE) Cohort Study is a multicenter collaborative network established with the aim of improving the understanding of juvenile SLE. The present study was undertaken to describe the clinical manifestations and disease course in patients with juvenile SLE from this large, national inception cohort. METHODS: Detailed data on clinical phenotype were collected at baseline and at regular clinic reviews and annual followup assessments in 232 patients from 14 centers across the UK over 4.5 years. Patients with SLE were identified according to the American College of Rheumatology (ACR) SLE classification criteria. The present cohort comprised children with juvenile SLE (n=198) whose diagnosis fulfilled ≥4 of the ACR criteria for SLE. RESULTS: Among patients with juvenile SLE, the female:male sex distribution was 5.6:1 and the median age at diagnosis was 12.6 years (interquartile range 10.4-14.5 years). Male patients were younger than female patients (P<0.01). Standardized ethnicity data demonstrated a greater risk of juvenile SLE in non-Caucasian UK patients (P<0.05). Scores on the pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index demonstrated significantly increased frequencies of musculoskeletal (82%), renal (80%), hematologic (91%), immunologic (54%), and neurologic (26%) involvement among the patients over time. A large proportion of the patients (93%) were taking steroids and 24% of the patients required treatment with cyclophosphamide. Disease damage was common, with 28% of the patients having a Systemic Lupus International Collaborating Clinics/ACR damage score of ≥1. CONCLUSION: The data on these patients from the UK JSLE Cohort Study, comprising one of the largest national inception cohorts of patients with juvenile SLE to date, indicate that severe organ involvement and significant disease activity are primary characteristics in children with juvenile SLE. In addition, accumulation of disease-associated damage could be seen.

Frequent discordance between clinical and musculoskeletal ultrasound examinations of foot disease in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the levels of agreement from independent clinical examination (CE) by a pediatric rheumatologist and podiatrist and an ultrasound (US) examination of articular and periarticular foot disease in juvenile idiopathic arthritis (JIA). METHODS: Thirty patients with JIA and a history of foot disease underwent CE and US examination of 24 foot joints, 10 tendons, and 6 periarticular soft tissues. Each site was examined independently by a rheumatologist and a podiatrist for synovitis and tenderness/swelling. The same sites were examined independently by a sonographer for effusion, synovial hypertrophy, power Doppler (PD) signal, tenosynovitis, or abnormal tendon thickening. Agreement was estimated using Cohen's unweighted kappa with corresponding 95% confidence intervals. RESULTS: Seven hundred twenty joints, 300 tendons, and 180 soft tissue sites were examined. Clinically detected synovitis, tenderness, and swelling were recorded in 42 (5.8%), 78 (10.8%), and 73 joints (10.1%), respectively. US-detected effusions, synovial hypertrophy, and PD signal were recorded in 88 (12.2%), 47 (6.5%), and 12 joints (1.7%), respectively. Subclinical foot disease was found in 52 joints (7.2%), 5 tendons (1.6%), and 4 soft tissue sites (2.2%). Agreement was consistently less than moderate (κ = <0.4) for each clinical and US interaction. CONCLUSION: This study uniquely demonstrated an interprofessional evaluation of foot disease in JIA. Interobserver agreement was less than acceptable for CE versus US, and subclinical foot disease is common in joints and periarticular soft tissues. US may be a useful tool to aid CE of the foot in JIA patients.

Agreement between proxy and adolescent assessment of disability, pain, and well-being in juvenile idiopathic arthritis.

OBJECTIVES: Adolescents with juvenile idiopathic arthritis have demonstrated substantial disagreement with their proxy's assessment of their disability, pain, and well-being. Our objective was to describe the clinical and psychological factors associated with discordance. STUDY DESIGN: This analysis included 204 proxy-adolescent (median age, 13 years) dyads that completed a Childhood Health Assessment Questionnaire for disability with 100-mm visual analogue scales for pain and well-being. Depressive symptoms in adolescents were measured by the Mood and Feelings Questionnaire and in proxies the General Health Questionnaire. Disagreement was assessed using Bland-Altman plots. Associations with discordance were identified using logistic regression analyses. RESULTS: There was higher agreement for disability (84%) than for pain (71%) and well-being (66%). Regression analyses found no association between age, sex, or disease duration and disagreement. However, relationships between disease activity and disagreement in outcomes were identified. Independent associations were found between increasing Mood and Feelings Questionnaire scores and disagreement in pain and well-being. CONCLUSIONS: Proxy and adolescent reports of pain and well-being are more likely to disagree in those with severe disease. Adolescents who report depressive symptoms are also more likely to disagree with their proxy. The reasons for these are multifactorial, and considerations of both reports are important when assessing outcomes in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA): a screening study to measure class II skeletal pattern, TMJ PDS and use of systemic corticosteroids.

OBJECTIVE: To screen patients with oligoarticular and polyarticular forms of Juvenile Idiopathic Arthritis (JIA) to determine (i) the severity of their class II skeletal pattern; (ii) temporomandibular joint signs and symptoms and (iii) use of systemic corticosteroids. DESIGN: Cross-sectional screening. SUBJECTS AND SETTING: Sixty-eight children with JIA aged between 9 and 16 years old who were screened at four regional treatment centres in the UK. METHOD: Patients were screened clinically and radiographically for the presence of class II skeletal pattern and temporomandibular (TMJ) pain dysfunction syndrome. In addition, the JIA sub-type and history of disease activity and medication were recorded. MAIN OUTCOME MEASURES: Class II skeletal pattern, TMJ signs and symptoms, use of systemic corticosteroids. RESULTS: The mean ANB values were 4.2 degrees (SD = 2.9 degrees) in the oligoarticular group and 5.1 degrees (SD = 3.8 degrees) in the polyarticular group. Just under one-third of children had a moderate or severe class II skeletal pattern and a further quarter of children had a mild class II skeletal pattern. Clinical signs and symptoms of temporomandibular joint pain dysfunction syndrome were low (<20%), except for crepitus and click which affected between 24 and 40% of JIA children. Radiographically, 57% of oligoarticular and 77% of polyarticular cases exhibited condylar erosion. Use of systemic corticosteroids varied between centres, but overall, was prescribed more in polyarticular cases (P = 0.001). CONCLUSIONS: Just under one-third of oligoarticular and polyarticular JIA patients exhibited a moderate or severe class II skeletal pattern. It is, therefore, likely that any future clinical trial to investigate the effect of functional appliance treatment in JIA patients, will need multicentre co-operation to fulfil potential sample size requirements. Clinical signs and symptoms of temporomandibular joint pain dysfunction syndrome were low except for crepitus and click. However, radiographic evidence of condylar erosion was high particularly in the polyarticular group. Use of systemic corticosteroids was prescribed more in polyarticular cases and this is likely to reflect the severity of the disease.